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ArticleMay 26, 2011

Structure-Based Design of Novel Boronic Acid-Based Inhibitors of Autotaxin
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Journal of Medicinal Chemistry

Cite this: J. Med. Chem. 2011, 54, 13, 4619–4626

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https://doi.org/10.1021/jm200310q

Published May 26, 2011

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Abstract

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Autotaxin (ATX) is a secreted phosphodiesterase that hydrolyzes the abundant phospholipid lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in inflammation, fibrosis, and tumor progression, rendering ATX an attractive drug target. We recently described a boronic acid-based inhibitor of ATX, named HA155 (1). Here, we report the design of new inhibitors based on the crystal structure of ATX in complex with inhibitor 1. Furthermore, we describe the syntheses and activities of these new inhibitors, whose potencies can be explained by structural data. To understand the difference in activity between two different isomers with nanomolar potencies, we performed molecular docking experiments. Intriguingly, molecular docking suggested a remarkable binding pose for one of the isomers, which differs from the original binding pose of inhibitor 1 for ATX, opening further options for inhibitor design.

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† Author-Status

Deceased.

Introduction

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The secreted glycoprotein autotaxin (ATX) is a phosphodiesterase responsible for the hydrolysis of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) and choline, as depicted in Scheme 1. (1, 2) The bioactive lipid LPA stimulates migration, proliferation and survival of cells by activating specific G protein-coupled receptors. (3) The ATX-LPA signaling axis is involved in cancer, inflammation and fibrotic disease. (4-6) Potent and selective ATX inhibitors are needed to elucidate the contribution of ATX action to signaling cascades that may result in disease in case of malfunction.

Scheme 1. Autotaxin (ATX) is Responsible for Hydrolyzing the Lipid Lysophosphatidylcholine (LPC) into Lysophosphatidic Acid (LPA) and Choline

ATX, also known as eNPP2, is a unique member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (eNPP) family of proteins. It is the only family member capable of producing LPA by hydrolysis of LPC. (7) Recently reported crystal structures of mouse (8) and rat (9) ATX confirmed that a threonine residue and two zinc ions are necessary for activity of ATX. (10) From these structures, it could be concluded that ATX hydrolyzes its substrates through a typical alkaline phosphatase/phosphodiesterase mechanism. (11, 12) Furthermore, these structures showed that ATX specifically binds its lipid substrates in a hydrophobic pocket extending from the active site of ATX. This pocket accommodates the alkyl chain of the lipids in different poses as was also shown in various crystal structures. (8)

Recently, we described the discovery of a boronic acid-based ATX inhibitors that helped to reveal the short half-life (∼5 min) of LPA in vivo. (13, 14) We introduced a boronic acid moiety in the inhibitor structure to rationally target the threonine oxygen nucleophile of ATX with a hard matching Lewis acid. The crystal structure of ATX in complex with HA155 (1) (9) confirmed our hypothesis that this inhibitor targets the threonine oxygen nucleophile in the ATX active site via the boronic acid moiety, while the hydrophobic 4-fluorobenzyl moiety of inhibitor 1 targets the hydrophobic pocket responsible for lipid binding (Figure 1).

Figure 1. ATX structure liganded with inhibitor 1 (PDB ID 2XRG). (A) Surface representation of ATX with inhibitor 1 (magenta). (B) Binding of inhibitor 1 to the threonine oxygen nucleophile and two zinc ions. (C) Visualizing the ether linker of inhibitor 1 bound to ATX. (D) Visualizing the degree of freedom for the thiazolidine-2,4-dione core of inhibitor 1 in the ATX binding site.

Here, we report a number of synthetic routes, systematically substituting linkers and the thiazolidine-2,4-dione core in 1, while keeping the boronic acid moiety untouched. The observed structure–activity relations could well be explained from the ATX structure in complex with inhibitor 1. A remarkable binding pose of a novel inhibitor, as predicted from molecular docking experiments, suggests additional avenues for further inhibitor design.

Results and Discussion

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Design of Inhibitors

The structure of inhibitor 1 bound to the ATX active site (Figure 1) showed that its 4-fluorobenzyl moiety binds into the hydrophobic lipid binding pocket of ATX (Figure 1C,D). (9) This pocket also accommodates the lipid tail of LPA, the hydrolysis product of LPC. (8) The thiazolidine-2,4-dione core of 1 and the conjugated aromatic ring are located between the hydrophobic pocket and the catalytic site (Figure 1D). The ether linker, bridging the two aromatic rings in 1, and especially a methylene and arylboronic acid moiety are well accessible to solvent (Figure 1C). Binding of inhibitor 1 to the ATX active site is predominately driven by hydrophobic interactions (the interaction interface is approximately 500 Å²) and by the boronic acid binding to the threonine oxygen nucleophile of ATX. (9) The boron–oxygen distance observed is ∼1.6 Å, which is consistent with a covalent bond. As expected, this binding is reversible evidenced by the fact that ATX activity can be fully restored upon washing out the inhibitor. (13) In addition, one of the boronic acid hydroxyl moieties is tethered by the two zinc ions in the ATX active site. Thus, the boronic acid moiety targets not only the threonine oxygen nucleophile, but also the two zinc ions that are essential for catalytic activity of ATX (Figure 1B). Remarkably, there are no hydrogen bonds or salt bridges that participate in binding of inhibitor 1 to ATX. Inhibitor 1 is locked in a pose with reduced molecular flexibility, forming an ideal starting point for a structure-based approach to further modifications.

Previously, we determined that the 4-fluorobenzyl moiety is preferred from over 40 benzylic substituents tested. (13) For this reason, we left the 4-fluorobenzyl moiety untouched in this study. We investigated new design options, starting by modifying the ether linker in inhibitor 1. We decided to replace the ether linkage (OCH₂) with various amides, an amine, and an E-configured double bond (CONH (17), CONCH₂ (18), NHCO (19), NHCH₂ (36), and (E)-CH═CH (20); see Table 1). The thiazolidine-2,4-dione core was investigated next. We substituted the sulfur atom present with (substituted) amino and methylene moieties (NH (26), NCH₃ (28), or CH₂ (32)) (Table 2). The carbon double bond conjugated to the thiazolidine-2,4-dione carbonyl moiety forms a possible Michael acceptor. Although this Michael acceptor is resistant to nucleophilic additions in vitro (Supporting Information Figure S1) it may be a biologically active Michael acceptor in vivo, and therefore, we investigated its removal.

Table 1. IC₅₀ Values of the Inhibitors Resulting from the Linker Modification

^{Table a}

IC₅₀ values have been determined in the choline release assay using 40 μM LPC and 10 nM ATX. The dose–response curve of inhibitor 17 shows biphasic curve (see Supporting Information Figure S2).

Table 2. IC₅₀ Values of the Inhibitors Resulting from the Core Modification

^{Table a}

IC₅₀ values have been determined in the choline release assay using 40 μM LPC and 10 nM ATX. E-28 contains 20% of the Z-isomer.

Chemical Synthesis of Modified Inhibitors

We first explored synthetic routes to replace the ether linkage in 1. The synthesis of target molecules 17–20 (Scheme 2) starts with palladium catalyzed borylation of appropriate aldehydes via a Suzuki-Miyaura reaction (15) as depicted in Scheme 2 (for syntheses of aldehydes 2–6 see Supporting Information). This reaction smoothly provided intermediates 7–11. Next, the pinacol protecting group was hydrolyzed under acidic conditions and oxidatively destroyed by NaIO₄ giving boronic acid aldehydes 12–16. In the final step 3-(4-fluorobenzyl)thiazolidine-2,4-dione is reacted with the boronic acid aldehyde by Knoevenagel condensation to selectively give the Z-isomer of the final products (1 and 17–20).

Scheme 2. Synthetic Route Towards Linker Modified Inhibitors

In order to remove the potential Michael acceptor present, we reduced the double bond in inhibitor 1 using hydrogen and palladium on carbon (Scheme 3A), to give compound 21. To reduce the carbonyl moiety also in the thiazolidine-2,4-dione core of 1, we used NaBH₄ resulting in hemiaminal 22. After addition of sulfuric acid to the reaction mixture to eliminate the hydroxyl moiety in 22, unsaturated inhibitor 23 was obtained.

Scheme 3. Synthetic Routes Towards Core Modified Inhibitors

For the syntheses of imidazolidine-2,4-dione-based inhibitors 26 and 28, imidazolidine-2,4-dione (24) was mono N-alkylated with 4-fluorobenzyl bromide to give intermediate 25 (Scheme 3B). Reaction of 25 by a Knoevenagel condensation with aldehyde 12 selectively resulted in the formation of the Z-isomer of 26. In parallel, intermediate 25 was methylated to give compound 27. Finally, 27 was condensed with aldehyde 12 resulting in target molecule 28. Both the Z- and E-isomers were formed in a 1:4 (Z:E) ratio. To obtain and isolate solely the Z-isomer 28, we N-methylated compound 26.

Core-hopping from thiazolidine-2,4-dione to pyrrolidine-2,5-dione is depicted in Scheme 3C. The route starts with the formation of a Wittig reagent starting from 2,5-pyrroledione (29), which is reacted with triphenylphosphine to form ylide 30. (16) The Wittig reaction of the carbonyl stabilized ylide 30 with aldehyde 12 selectively leads to the E-isomer of intermediate 31 as expected. Finally, compound 31 is N-alkylated with 4-fluorobenzyl bromide resulting in the pyrrolidine-2,5-dione product 32.

For the synthesis of a final tetrahydroisoquinoline-based core with a more rigid structure, the secondary amine in R- or S-tetrahydroisoquinoline 33 is reacted with 4-fluorobenzyl isocyanate in the presence of sodium hydroxide to form a urea intermediate. The imidazolidine ring is then formed upon acidification with hydrochloric acid, resulting in compound R- or S-34. In the final step, intermediate 34 is O-alkylated with 4-(bromomethyl)phenylboronic acid resulting in R- or S-35.

Structure–Activity Relations of Inhibitors and Autotaxin

Activity of the new molecules resulting from the linker and core modifications were determined in an LPC hydrolysis assay described previously, (13, 17) in which ATX-mediated release of choline from LPC is detected by a two-step enzymatic colorimetric reaction. The IC₅₀ values observed for inhibitors with modified linkers and cores are listed in Tables 1 and 2.

When we replaced the ether moiety (OCH₂, inhibitor 1, IC₅₀ = 5.7 nM) for an amide linker (CONH, 17), we observed a significant loss of activity (IC₅₀ = 147 nM). The dose–response curve of inhibitor 17 shows a biphasic curve (18) that could suggest several binding sites of this inhibitor for ATX (Supporting Information Figure S2). Expanding the CONH linker (17) to a more flexible CONHCH₂ linker (18) improved the IC₅₀ value (71 nM) by 2-fold compared to inhibitor 17. Reversing the amide linker in 17 to yield compound 19, results in high potency (IC₅₀ = 10 nM), similar to inhibitor 1. However, inhibitor 19 is not able to achieve full inhibition, and 10% residual ATX activity is observed (Supporting Information Figure S3). Apparently, a more rigid amide linker results in suboptimal binding of the inhibitor. Therefore, we synthesized the more flexible amine analogue 36 (for the synthesis of inhibitor 36 see Supporting Information). This resulted indeed in a potent inhibitor (IC₅₀ = 8.3 nM), similar to 1, and with no residual ATX activity (Supporting Information Figure S3). Introduction of an (E)-CH═CH linker resulted in compound 20, which was inactive in the nanomolar range (IC₅₀ > 5 μM). This observation can be explained by the fact that the two aromatic rings linked with a flexible OCH₂ linker in inhibitor 1 are positioned in an angle of roughly 90° in the ATX structure (see Figure 1B) which cannot be achieved by the (E)-CH═CH linker due to its rigid planar conformation.

Next, we explored the activity of compounds with a modified core. Reducing the carbon double bond in 1 resulted in little loss of activity in 21 with an IC₅₀ value of 25 nM. Thus, although rigidity is preferred, the Michael acceptor can easily be removed without significant loss in activity. Reducing both the carbon double bond and the neighboring carbonyl in inhibitor 1 to hemiaminal 22, led to a significant loss in potency (IC₅₀ = 1.6 μM). Inhibitor 23, where the hydroxyl moiety in compound 22 is removed is not very potent either (IC₅₀ = 683 nM), indicates that the carbonyl moiety is important for binding. It appears from the crystal structure of inhibitor 1 bound to ATX that π-stacking between the phenyl ring of phenylalanine residue 274 (F274) and the carbonyl moiety in 1 is very likely seen their distance (4.1 Å, Supporting Information Figure S4). (19) By removing the carbonyl moiety in 1 or by changing it into a hydroxyl moiety, π-stacking will be lost resulting in lower potencies as observed for inhibitor 22 and 23.

The sulfur heteroatom in the thiazolidine-2,4-dione core was replaced with other atoms and moieties. We started by replacing the sulfur atom in 1 with a methylene moiety gives compound 32 with an IC₅₀ value of 7.3 nM, comparable to inhibitor 1. Replacement of the sulfur atom for an amino group (26, IC₅₀ = 26 nM) resulted in little loss in activity compared to inhibitor 1. When the amine in compound 26 is methylated, potency for the resulting inhibitor Z-28 (IC₅₀ = 6.7 nM) is slightly increased. Interestingly, the E-isomer of 28 (IC₅₀ = 5.3 nM) is marginally more potent than Z-28 or inhibitor 1, a finding that we did not anticipate.

Intrigued by the characteristics of inhibitors Z-28 and E-28, we decided to calculate likely binding poses. For this purpose, we used the Glide docking software. (20-22) To validate our docking approach where we constrain the boronic acid moiety, we first docked inhibitor 1 back into the ATX active site, resulting in a pose (Figure 2B) very similar to the original crystal structure (Figure 2A) with a rmsd value of 1.1 Å (for superimposed image see Supporting Information Figure S5). Next, we docked the Z- and E-isomers of inhibitor 28 (the three best docking poses are depicted in Figure 2C and D). The docking poses of Z-28 correspond to the pose of inhibitor 1 in the ATX structure. However, two of the best three docking poses for E-28 suggest that the 4-fluorobenzyl moiety likely binds to a different area in the hydrophobic pocket (Figure 2D). The imidazolidine-2,4-dione core of E-28 is flipped around the double bond axis in the ATX binding site compared to its Z-isomer (compare Figure 2C with D). This observation is in agreement with the conformations of both isomers. In addition, the binding poses of Z-28 and E-28 resulting from our docking study suggest that the current 4-fluorobenzyl moiety could be expanded from the methylene moiety in the 4-fluorobenzyl substituent with other substituents in future ATX inhibitors.

Figure 2. (A) Focus from inside the protein on the thiazolidine-2,4-dione core of inhibitor 1 bound to ATX. (B) Inhibitor 1 docked into the active site of ATX to validate our docking approach. (C) The three best docking poses for the Z-isomer of 28. (D) The three best docking poses for the E-isomer of 28. Docking poses were generated using the docking program *Glide*.

Finally, we evaluated inhibitors in which we introduced a rigidified three-ring system (Table 2) incorporating a tetrahydroisoquinoline motif that we deemed likely to bind. This modification avoids the presence of a Michael acceptor, while introducing rigidity and a new core structure. This modification resulted in the chiral inhibitor 35, which is still very potent although some activity is lost compared to 1. No significant difference is observed in potency for either the S or R enantiomers of inhibitor 35, with IC₅₀ values of 55 and 59 nM, respectively.

In summary, we explored structure–activity relations building on boronic acid-based ATX inhibitor 1, which resulted in a number of potent inhibitors. We used the crystal structure of ATX liganded with inhibitor 1 (9) to explain the structure–activity relationships observed for a rational inhibitor modification approach. Our results suggest that this approach allows rapid structure guided modification. Finally, molecular docking efforts proved useful to explain unexpected high potency of E-isomer 28 and suggested that the lipophilic pocket near the ATX active site may be better exploited in the future for the design of new inhibitors.

Experimental Section

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Chemistry

The R and S enantiomers of building block 33 were purchased from CSPS Pharmaceuticals, San Diego, USA. All other chemicals were obtained from Sigma-Aldrich and used without further purification unless otherwise noted. Analytical thin layer chromatography was performed on aluminum sheets precoated with silica gel 60 F₂₅₄. Column chromatography was carried out on silica gel (0.035–0.070, 90 Å, Acros).

For isolation by centrifugation a Heraeus Multifuge 3 _S-R centrifuge was used. Products were spun at 4400g, at 298 K for 5 min. Nuclear magnetic resonance spectra (¹H and ¹³C NMR) were determined in deuterated dimethyl sulfoxide (d₆-DMSO) using a Bruker Avance 300 (¹H, 300 MHz; ¹³C, 75 MHz) at 298 K, unless indicated otherwise. Peak shapes are indicated with the symbols ‘d’ (doublet), ‘dd’ (double doublet), ‘s’ (singlet), ‘bs’ (broad singlet), and ‘m’ (multiplet). Chemical shifts (δ) are given in ppm and coupling constants J in Hz. Dimethyl sulfoxide (δ_H = 2.50 ppm; δ_C = 39.51 ppm) was used as internal reference.

The purity of all tested compounds was determined by high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS) and was greater than 95%. HPLC-MS measurements were performed on a system equipped with a Waters 2795 Separation Module (Alliance HT), Waters 2996 Photodiode Array Detector (190–750 nm), Atlantis T3 C18 column (2.1 × 100 mm, 3 μm), and an LCT Orthogonal Acceleration Time of Flight Mass Spectrometer. Samples were run at a flow rate of 0.40 mL min^–1 at 313 K, using gradient elution (water/acetonitrile/formic acid) from 950/50/1 (v/v/v) to 50/950/1 (v/v/v).

The preparative HPLC system was equipped with a Waters 1525 Binary HPLC Pump, a Waters 2487 Dual λ Absorbance Detector, and an Atlantis C18 column (19 × 250 mm, 10 μm). Samples were run at a flow rate of 18 mL min^–1 using gradient elution (water/acetonitrile) from 60/40 (v/v) to 10/90 (v/v).

General Procedure for Borylation of Aldehydes and Pinacol Deprotection (12–16)

In a dry flask, bis(pinacolato)diboron (1.34 g, 5.28 mmol), the appropriate aldehyde (1.80 mmol) and potassium acetate (0.542 g, 5.52 mmol) were added to a solution of Pd(dppf)Cl₂ (46.6 mg, 0.0637 mmol) in dimethylformamide (15 mL). The reaction mixture was stirred under an atmosphere of argon for 18 h at 353 K. The reaction mixture was filtered over Hyflo Super Cel medium and diluted with ethyl acetate (100 mL). The solution was washed with brine (50 and 25 mL), dried over magnesium sulfate, and concentrated.

The crude product was dissolved in tetrahydrofuran (11 mL) and sodium periodate (2.22 g, 10.4 mmol) and water (2.8 mL) were added. After stirring for 30 min, 1 M hydrochloric acid (1.1 mL) was added, and after 2 h, additional sodium periodate (1.17 g, 5.47 mmol) was added and the solution was stirred for another 2 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL). The water layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, and the solution was concentrated under vacuum resulting in a light yellow solid. The resulting product was used without further purification.

(4-((4-Formylphenoxy)methyl)phenyl)boronic Acid (12)

Yield: 70%. ¹H NMR: δ = 9.86 (s, 1H), 8.09 (s, 1H), 7.87 (d, J = 8.8, 1H), 7.82 (d, J = 8.1, 1H), 7.42 (d, J = 8.1, 1H), 7.20 (d, J = 8.7, 1H), 5.24 (s, 1H). ¹³C NMR: δ = 191.75, 163.73, 138.49, 134.74, 132.26, 130.22, 127.15, 115.76, 70.09, 39.95 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 257.10, obs. 257.10.

For experimental details of compounds 13–16, see Supporting Information.

General Method for Knoevenagel Condensation (1, 17–20, 26, and E-28)

To a solution of 3-(4-fluorobenzyl)thiazolidine-2,4-dione (0.293 mmol) in ethanol (2.5 mL), piperidine (20 μL, 0.207 mmol), and the appropriate aldehyde (0.352 mmol) were added and the solution was refluxed for 22 h.

(Z)-4-[(4-{[3-(4-Fluorobenzyl)-2,4-dioxo-1,3-thiazolan-5-yliden]methyl}phenoxy) methyl]benzene Boronic Acid (1)

Upon cooling the reaction mixture to room temperature, the product precipitated out of solution. Dissolving the product in dimethyl sulfoxide and precipitating it with 0.5 M hydrochloric acid resulted in pure compound. Yield: 81%. ¹H NMR: δ = 8.03 (s, 2H), 7.92 (s, 1H), 7.80 (d, J = 8.1, 2H), 7.60 (d, J = 8.9, 2H), 7.41 (d, J = 8.0, 2H), 7.39–7.31 (m, J = 5.5, 8.8, 2H), 7.26–7.09 (m, J = 4.5, 8.9, 4H), 5.21 (s, 2H), 4.82 (s, 2H). ¹³C NMR: δ = 167.38, 165.59, 161.66 (d, ¹J_CF = 244), 160.33, 138.19, 134.28, 133.48, 132.33, 131.81 (d, ⁴J_CF = 3), 129.95 (d, ³J_CF = 8), 126.67, 125.55, 117.89, 115.81, 115.47 (d, ²J_CF = 21), 69.52, 43.90 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 464.11, obs. 464.19.

For experimental details of compounds 17–20, 26, and E-28 see Supporting Information.

(4-((4-((3-(4-Fluorobenzyl)-2,4-dioxothiazolidin-5-yl)methyl)phenoxy)methyl) phenyl)boronic Acid (21)

A mixture of compound 1 (50.1 mg, 0.108 mmol) and 10 wt % Pd/C (24.0 mg) in degassed methanol (3 mL) was stirred under a hydrogen atmosphere for 2 h. Extra 10 wt % Pd/C was added (12.0 mg) and the reaction was allowed to continue for one night. The mixture was filtrated and concentrated to dryness. Preparative HPLC afforded the title compound. Yield: 18.3 mg, 77%. ¹H NMR: δ = 8.03 (s, 2H), 7.80 (d, J = 8.1, 2H), 7.39 (d, J = 8.1, 2H), 7.28–6.99 (m, 6H), 6.88 (d, J = 8.7, 2H), 5.06 (s, 2H), 5.00 (dd, J = 4.4, 8.0, 1H), 4.60 (dd, J = 15.0, 21.5, 2H), 3.14 (dd, J = 8.0, 14.2, 1H). ¹³C NMR: δ = 173.71, 171.00, 161.50 (d, ¹J_CF = 244), 157.44, 138.74, 134.16, 131.58 (d, ⁴J_CF = 3), 130.56, 129.66 (d, ³J_CF = 8), 127.98, 126.52, 115.21 (d, ²J_CF = 21), 114.57, 69.12, 50.94, 43.56, 35.79 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 466.13, obs. 466.25, [M-H₂O+H]⁺ calc. 448.12, obs. 448.23.

(4-((4-((3-(4-Fluorobenzyl)-4-hydroxy-2-oxothiazolidin-5-yl)methyl)phenoxy) methyl)phenyl)boronic Acid (22)

To a solution of compound 1 (50.0 mg, 0.108 mmol) in dimethyl sulfoxide (0.5 mL), sodium borohydride (16.3 mg, 0.430 mmol) was slowly added. After 9 h of stirring, the reaction mixture was diluted with ethyl acetate (4 mL) and was washed with water (2 × 2 mL). The organic layer was dried over calcium chloride and concentrated in vacuo, resulting in the title compound. Yield: 30.2 mg, 60%. ¹H NMR: δ = 8.06 (s, 2H), 7.80 (d, J = 8.1, 2H), 7.39 (d, J = 8.0, 2H), 7.36 – 7.11 (m, 5H), 6.94 (d, J = 8.7, 2H), 6.87 (d, J = 8.7, 2H), 6.71 (d, J = 6.2, 1H), 5.06 (s, 2H), 4.72 (dd, J = 7.7, 15.1, 1H), 4.10 (d, J = 15.1, 1H), 3.67 (t, J = 7.9, 1H), 3.35 (s, 1H), 2.81 (dd, J = 7.3, 13.9, 1H), 2.70 (dd, J = 8.4, 13.9, 1H). ¹³C NMR: δ = 169.70, 161.55 (d, ¹J_CF = 244), 157.13, 138.85, 134.15, 133.14 (d, ⁴J_CF = 3.0), 130.01, 130.00 (d, ³J_CF = 8), 129.73, 126.54, 115.38 (d, ²J_CF = 21), 114.64, 84.02, 69.11, 51.42, 44.02, 39.65. (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 468.15, obs. 468.23.

(4-((4-((3-(4-Fluorobenzyl)-2-oxo-2,3-dihydrothiazol-5-yl)methyl)phenoxy) methyl)phenyl)boronic Acid (23)

To a solution of compound 1 (45.7 mg, 0.0989 mmol) in dimethyl sulfoxide (0.75 mL), sodium borohydride (29.1 mg, 0.769 mmol) was slowly added. After 7 h of stirring the reaction mixture, concentrated sulfuric acid (2 × 50 μL) was added over a 15 min interval. The reaction mixture was stirred for an additional 5 h. Ethyl acetate (25 mL) was added and the mixture was washed with water (4 × 10 mL). The organic layer was dried over calcium chloride and concentrated in vacuo, affording pure compound 23. Yield: 31.8 mg, 72%. ¹H NMR: δ = 8.05 (s, 2H), 7.79 (d, J = 8.1, 2H), 7.38 (d, J = 8.1, 2H), 7.36–7.16 (m, 4H), 7.13 (d, J = 8.7, 2H), 6.95 (d, J = 8.7, 2H), 6.87 (s, 1H), 5.07 (s, 2H), 4.80 (s, 2H), 3.73 (s, 2H). ¹³C NMR: δ = 170.43, 161.61 (d, ¹J_CF = 244), 157.13, 138.85, 134.17, 133.10 (d, ⁴J_CF = 3), 130.63, 130.63, 129.76 (d, ³J_CF = 8), 129.42, 126.48, 121.56, 117.78, 115.50 (d, ²J_CF = 21), 114.86, 69.16, 46.78, 32.91 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 450.13, obs. 450.22.

3-(4-Fluorobenzyl)imidazolidine-2,4-dione (25)

To a cooled solution (273 K) of hydantoin (8.01 g, 80.1 mmol) in dimethylformamide (140 mL) sodium hydride (60% in oil, 1.80 g, 45.0 mmol) was added. A solution of 1-(bromomethyl)-4-fluorobenzene (5.0 mL, 41 mmol) in dimethylformamide (5 mL) was added to the reaction mixture. The mixture was allowed to warm up to room temperature and was stirred for 6 h. Then, the mixture was poured into water (200 mL) and hexane (200 mL) was added. After a night at 277 K, the precipitate was filtered and dried to give a white solid. Yield: 4.7 g, 56%. ¹H NMR: δ = 8.14 (s, 1H), 7.45–7.21 (m, 1H), 7.26–7.09 (m, 1H), 4.51 (s, 2H), 3.97 (s, 2H). ¹³C NMR: δ = 171.91, 161.45 (d, ¹J_CF = 244), 157.29, 133.04 (d, ⁴J_CF = 3), 129.66 (d, ³J_CF = 8), 115.21 (d, ²J_CF = 21), 46.00, 40.29. MS: m/z [M+H]⁺ calc. 209.07, obs. 208.93.

3-(4-Fluorobenzyl)-1-methylimidazolidine-2,4-dione (27)

To a cooled solution (273 K) of 3-(4-fluorobenzyl)imidazolidine-2,4-dione (98.1 mg, 0.471 mmol) in dimethylformamide (0.5 mL), sodium hydride (60% in oil, 21.1 mg, 0.530 mmol) was added. Subsequently, iodomethane (33 μL, 0.53 mmol) was added to the reaction mixture. The mixture was allowed to warm up to room temperature and was stirred for 3 h. Then, the mixture was poured into ice water (2.5 mL) and hexane (2.5 mL) was added. After a night at 277 K, the precipitate was filtered and dried to give a white solid. Yield: 75 mg, 72%. ¹H NMR: δ = 7.34–7.12 (m, 4H), 4.52 (s, 2H), 4.01 (s, 2H), 2.86 (s, 3H). ¹³C NMR: δ = 170.20, 161.46 (d, ¹J_CF = 244), 156.24, 132.92 (d, ⁴J_CF = 3), 129.68 (d, ³J_CF = 8), 115.21 (d, ²J_CF = 21), 51.36, 40.74, 29.21. MS: m/z [M+H]⁺ calc. 223.09, obs. 223.06.

(Z)-(4-((4-((1-(4-Fluorobenzyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl) phenoxy)methyl)phenyl)boronic Acid (Z-28)

To a cooled solution (273 K) of hydantoine 26 (10.1 mg, 0.0224 mmol) and sodium hydride (60% in oil, 1.46 mg, 0.0365 mmol) in DMF (0.15 mL), iodomethane (2.25 μL, 0.0361 mmol) was added. The mixture was allowed to warm up to room temperature and was stirred for 4 h. Final product was isolated by using preparative HPLC. Z-configuration confirmed by the chemical shift of the vinyl and methyl proton reported in literature. (23)

Yield: 6.97 mg, 68%. ¹H NMR: δ = 8.11 (s, 1H), 7.80 (d, J = 8.1, 2H), 7.50–7.30 (m, 6H), 7.26–7.10 (m, 2H), 7.05 (d, J = 8.8, 2H), 6.76 (s, 1H), 5.14 (s, 2H), 4.67 (s, 2H), 2.92 (s, 3H). ¹³C NMR: δ = 163.01, 159.92, 156.78 (d, ¹J_CF = 249), 138.52, 134.19, 132.55 (d, ⁴J_CF = 3), 131.28, 129.75 (d, ³J_CF = 8), 128.50, 126.58, 124.66, 115.31 (d, ²J_CF = 21), 114.55, 111.56, 69.30, 41.12, 30.35 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 461.17, obs. 461.12.

(E)-(4-((4-((2,5-Dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)boronic Acid (31)

To a heated (343 K) solution of compound 30 (159 mg, 0.442 mmol) (16) in methanol (5 mL) aldehyde 12 (106 mg, 0.414 mmol) was added. After 1 h of heating, the reaction mixture was cooled using an ice bath resulting in precipitation of the title compound. The precipitate was filtered and washed with ice-cold methanol resulting in compound 31. Yield: 88 mg, 63%. ¹H NMR: δ = 11.34 (s, 1H), 8.04 (s, 2H), 7.80 (d, J = 8.0, 2H), 7.57 (d, J = 8.9, 2H), 7.41 (d, J = 8.0, 2H), 7.33 (t, ⁴J = 2.1, 1H), 7.10 (d, J = 8.8, 2H), 5.19 (s, 2H), 3.60 (d, ⁴J = 2.2, 2H). ¹³C NMR: δ = 175.80, 172.09, 159.47, 138.42, 134.22, 132.00, 131.31, 126.96, 126.54, 124.16, 115.31, 69.31, 34.71 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 338.12, obs. 338.11.

(E)-(4-((4-((1-(4-Fluorobenzyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy) methyl)phenyl)boronic Acid (32)

To a solution of compound 31 (30 mg, 0.0890 mmol) in dimethylformamide (0.3 mL) sodium hydride (60% in oil, 3.65 mg, 0.0913 mmol) was added. After addition of 4-fluorobenzyl bromide (24 μL, 0.19 mmol), the reaction mixture was stirred for 4 h. In addition, potassium carbonate (2.04 mg, 0.0148 mmol) was added and the reaction mixture was stirred overnight. Then, the mixture was poured into ice water (0.9 mL) and hexane (0.3 mL) was added. After a night at 277 K, the precipitate was filtered, dried, and purified using preparative HPLC to give a white solid. E-Configuration confirmed by the chemical shift of the vinyl proton reported in literature. (16) Yield: 13 mg, 32%. ¹H NMR: δ = 8.04 (s, 2H), 7.80 (d, J = 8.1, 2H), 7.61 (d, J = 8.9, 2H), 7.45 (t, ⁴J = 2.1, 1H), 7.41 (d, J = 8.0, 2H), 7.38–7.29 (m, 2H), 7.23–7.04 (m, 4H), 5.19 (s, 2H), 4.66 (s, 2H), 3.74 (d, ⁴J = 2.1, 2H). ¹³C NMR: δ = 174.19, 170.59, 161.44 (d, ¹J_CF = 244), 159.65, 138.39, 134.22, 132.59 (d, ⁴J_CF = 3), 132.31, 132.17, 129.73 (d, ³J_CF = 8), 126.85, 126.54, 122.27, 115.36, 115.22 (d, ²J_CF = 21), 69.33, 40.71, 33.74 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 446.16, obs. 446.12.

(S)-2-(4-Fluorobenzyl)-7-hydroxy-10,10a-dihydroimidazo[1,5-b]isoquinoline-1,3(2H,5H)-dione (S-34)

Compound S-33 (100 mg, 0.518 mmol) was dissolved in a mixture of dioxane and water (3:1, 4 mL) and 30 wt % of sodium hydroxide solution was used to adjust the pH to 14. The reaction mixture was heated to 313 K and 4-fluorobenzyl isocyanate (100 μL, 0.785 mmol) was added. After 2 h of stirring, the mixture was cooled to room temperature and the resulting solid was removed using centrifugation. From the resulting solution, dioxane was evaporated and concentrated hydrochloric acid was used to adjust the pH to 1. After refluxing the reaction mixture for 2 h 30 min, it was cooled to 278 K affording a white precipitate. Washing the precipitate with ice-cold water (3 × 1 mL) afforded pure compound S-34. Yield: 30 mg, 18%. ¹H NMR: δ = 9.37 (s, 1H), 7.35–7.30 (m, 2H), 7.18–7.12 (m, 2H), 7.06–7.03 (m, 1H), 6.65–6.63 (m, 2H), 4.77 (d, J = 16.8, 1H), 4.58 (s, 2H), 4.32–4.27 (m, 2H), 3.05 (m, 1H), 2.82–2.64 (m, 1H). ¹³C NMR: δ = 172.76, 161.44 (d, ¹J_CF = 244), 156.07, 154.60, 132.82 (d, ⁴J_CF = 3), 132.35, 130.13, 129.51 (d, ³J_CF = 8), 121.45, 115.26 (d, ²J_CF = 21), 114.30, 112.67, 54.54, 41.23, 40.56, 29.02. MS: m/z [M+H]⁺ calc. 327.11, obs. 327.09.

(R)-2-(4-Fluorobenzyl)-7-hydroxy-10,10a-dihydroimidazo[1,5-b]isoquinoline-1,3(2H,5H)-dione (R-34)

For reaction details, see compound S-34. Yield: 29%. ¹H NMR, ¹³C NMR, and MS, see Supporting Information.

(S)-(4-(((2-(4-Fluorobenzyl)-1,3-dioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolin-7-yl)oxy)methyl)phenyl)boronic Acid (S-35)

To a heated solution (323 K) of compound S-34 (15.3 mg, 0.0469 mmol) in acetone (0.3 mL), potassium carbonate (10.2 mg, 0.0738 mmol) and 4-(bromomethyl)phenylboronic acid (12.4 mg, 0.0577 mmol) were added. After 4 h of stirring and heating, additional potassium carbonate (10.1 mg, 0.0730 mmol) was added and the suspension was stirred overnight. Finally, the reaction mixture was diluted with ethyl acetate and the organic layer was washed with 1 M hydrochloric acid (2 × 0.5 mL) and brine (0.5 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting solid was further purified using preparative HPLC affording pure compound S-35. Yield: 11 mg, 52%. ¹H NMR: δ = 8.06 (s, 2H), 7.78 (d, J = 8.1, 2H), 7.50–7.27 (m, 4H), 7.27–7.05 (m, 3H), 7.02–6.76 (m, 2H), 5.09 (s, 2H), 4.82 (d, J = 17.0, 1H), 4.58 (s, 2H), 4.42–4.20 (m, 2H), 3.19–3.02 (m, 1H), 2.80–2.71 (m, 1H). ¹³C NMR: δ = 172.72, 161.46 (d, ¹J_CF = 244), 157.09, 154.60, 138.74, 134.17, 132.81 (d, ⁴J_CF = 3), 132.60, 130.23, 129.55 (d, ³J_CF = 8), 126.49, 123.60, 115.28 (d, ²J_CF = 21), 113.87, 112.47, 69.20, 54.40, 41.30, 40.60, 29.00 (C–B(OH)₂ not visible). MS: m/z [M+H]⁺ calc. 461.17, obs. 461.14.

(R)-(4-(((2-(4-Fluorobenzyl)-1,3-dioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolin-7-yl)oxy)methyl)phenyl)boronic acid (R-35)

For reaction details, see compound S-35. Yield: 56%. ¹H NMR, ¹³C NMR, and MS, see Supporting Information.

Choline Release Assay. (13)

Measuring ATX activity using LPC (18:1) as substrate was determined as follows. In an opaque flat-bottom 96-wells plate (Greiner) was added 0.5 μL dimethyl sulfoxide containing inhibitor, to 25 μL recombinant ATX (∼20 nM) in Tris-HCl buffer (0.01% Triton X-100 and 50 mM Tris-HCl, pH 7.4). Finally, 25 μL of 80 μM LPC (18:1) in Tris-HCl buffer (10 mM MgCl₂, 10 mM CaCl₂, 0.01% Triton X-100 and 50 mM Tris-HCl, pH 7.4) was added to each well and the plate was incubated at 310 K. The above-described mixture with dimethyl sulfoxide alone was used as a control. LPC without ATX was taken as control for autohydrolysis of LPC. For each inhibitor, ten concentrations were measured covering a range of 0.01 to 30 μM to determine IC₅₀ values. After 4 h of incubation, 50 μL ABTS (2 mM) and horseradish peroxidase (5 U mL^–1) was added to the reaction mixture and absorbance was measured and used to correct for absorbance of the molecules. Finally, 50 μL choline oxidase (5 U mL^–1) in Tris-HCl (0.01% Triton X-100 and 50 mM Tris-HCl, pH 7.4) was added for colorimetric reaction. Absorbance was measured in a Perkin-Elmer Envision plate reader (λ = 405 nm). Data were analyzed using Graphpad Prism software.

In addition, the effect of the inhibitors on the enzymatic coloring reaction was investigated using 40 μM choline at 30 μM inhibitor using the above-described coloring reagents. The enzymatic coloring reaction was not effected by the inhibitors.

Docking Experiments, Protein, and Ligand Preparation

The X-ray structure of ATX in complex with inhibitor 1 (PDB ID: 2XRG) was used for the docking studies. The protein structure was prepared using the Schrödinger Suite 2010 Protein Preparation Wizard (with Epik 2.1, (24) Impact 5.6, and Prime 2.2). The initial 3D structures of the ligands were generated using LigPrep 2.4 and the ligand partial charges were ascribed using the OPLS2005 force-field as performed by Glide 5.6. (20-22) We defined the binding region by a 20 Å × 20 Å × 20 Å box centered on the central position of inhibitor 1 in the crystal ATX complex. We used positional constraints for the two oxygen atoms of the boronic acid and the arylic carbon direct next to the boron atom in inhibitor 1. The Glide Emodel score was used to rank the docking poses. Pictures were made using PyMOL 1.3.

Supporting Information

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Contains Michael acceptor study of inhibitor 1, dose–response curves of inhibitors 17, 19, and 36, image visualizing π-stacking of carbonyl inhibitor 1 with ATX residue F274, image of docked and X-ray pose of inhibitor 1 superimposed, experimental details of compounds 13–20, 26, and E-28, details on the syntheses of aldehydes 2–6 and amine linker-based inhibitor 36, and spectral data of all intermediates and target molecules. This material is available free of charge via the Internet at http://pubs.acs.org.

jm200310q_si_001.pdf (6.6 MB)

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Author Information

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Corresponding Author
- Huib Ovaa - ‡Division of Cell Biology, §Netherlands Proteomics Centre, and ∇Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Email: [email protected]
Authors
- Harald M. H. G. Albers - ‡Division of Cell Biology, §Netherlands Proteomics Centre, and ∇Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Loes J. D. Hendrickx - ‡Division of Cell Biology, §Netherlands Proteomics Centre, and ∇Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Rob J. P. van Tol - ‡Division of Cell Biology, §Netherlands Proteomics Centre, and ∇Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Jens Hausmann - ‡Division of Cell Biology, §Netherlands Proteomics Centre, and ∇Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Anastassis Perrakis - ‡Division of Cell Biology, §Netherlands Proteomics Centre, and ∇Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Acknowledgment

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In memory of Loes J. D. Hendrickx 06-01-1986/28-05-2010. We want to thank Irene Farre Gutierrez for helpful discussions. This work was supported by grants from The Netherlands Organization for Scientific Research (NWO), the Dutch Cancer Society (KWF), and The Netherlands Proteomics Centre supported by The Netherlands Genomics Initiative.

Non-Standard Abbreviations

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ABTS	2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)
ATX	autotaxin
HPLC-MS	high-performance liquid chromatography mass spectrometry
LPA	lysophosphatidic acid
LPC	lysophosphatidylcholine
eNPP	ectonucleotide pyrophosphatase and phosphodiesterase

References

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This article references 24 other publications.

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Identification of Human Plasma Lysophospholipase D, a Lysophosphatidic Acid-producing Enzyme, as Autotaxin, a Multifunctional Phosphodiesterase
Tokumura, Akira; Majima, Eiji; Kariya, Yuko; Tominaga, Kyoko; Kogure, Kentaro; Yasuda, Katsuhiko; Fukuzawa, Kenji
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We purified human plasma lysophospholipase D that produces physiol. active lysophosphatidic acid and showed that it is a sol. form of autotaxin, an ecto-nucleotide pyrophosphatase/phosphodiesterase, originally found as a tumor cell motility-stimulating factor. Its lower Km value for a lysophosphatidylcholine than that for a synthetic substrate of nucleotide suggests that lysophosphatidylcholine is a more likely physiol. substrate for autotaxin and that its predicted physiol. and pathophysiol. functions could be mediated by its activity to produce lysophosphate acid, an intercellular mediator. Recombinant autotaxin was found to have lysophospholipase D activity; its substrate specificity and metal ion requirement were the same as those of the purified plasma enzyme. The activity of lysophospholipase D for exogenous lysophosphatidylcholine in human serum was found to increase in normal pregnant women at the third trimester of pregnancy and to a higher extent in patients in threatened preterm delivery, suggesting its roles in induction of parturition.
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Autotaxin (ATX) is a tumor cell motility-stimulating factor, originally isolated from melanoma cell supernatants. ATX had been proposed to mediate its effects through 5'-nucleotide pyrophosphatase and phosphodiesterase activities. However, the ATX substrate mediating the increase in cellular motility remains to be identified. Here, we demonstrated that lysophospholipase D (lysoPLD) purified from fetal bovine serum, which catalyzes the prodn. of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC), is identical to ATX. The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate. LPA mediates multiple biol. functions including cytoskeletal reorganization, chemotaxis, and cell growth through activation of specific G protein-coupled receptors. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines. Moreover, we demonstrate that several cancer cell lines release significant amts. of LPC, a substrate for ATX, into the culture medium. The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine prodn. of LPA contributes to tumor cell motility, survival, and proliferation. It also provides potential novel targets for therapy of pathophysiol. states including cancer.
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Kanda, Hidenobu; Newton, Rebecca; Klein, Russell; Morita, Yuka; Gunn, Michael D.; Rosen, Steven D.
Nature Immunology (2008), 9 (4), 415-423CODEN: NIAMCZ; ISSN:1529-2908. (Nature Publishing Group)
The extracellular lysophospholipase D autotaxin (ATX) and its product, lysophosphatidic acid, have diverse functions in development and cancer, but little is known about their functions in the immune system. Here we found that ATX had high expression in the high endothelial venules of lymphoid organs and was secreted. Chemokine-activated lymphocytes expressed receptors with enhanced affinity for ATX, which provides a mechanism for targeting the secreted ATX to lymphocytes undergoing recruitment. Lysophosphatidic acid induced chemokinesis in T cells. I.v. injection of enzymically inactive ATX attenuated the homing of T cells to lymphoid tissues, probably through competition with endogenous ATX and exertion of a dominant neg. effect. These results support the idea of a new and general step in the homing cascade in which the ectoenzyme ATX facilitates the entry of lymphocytes into lymphoid organs.
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A review. Autotaxin (ATX), or nucleotide pyrophosphatase/phosphodiesterase 2 (NPP2), is an exo-enzyme originally identified as a tumor cell autocrine motility factor. ATX is unique among the NPPs in that it primarily functions as a lysophospholipase D, converting lysophosphatidylcholine into the lipid mediator lysophosphatidic acid (LPA). LPA acts on specific G protein-coupled receptors to elicit a wide range of cellular responses, ranging from cell proliferation and migration to neurite remodeling and cytokine prodn. While LPA signaling has been studied extensively over the last decade, we are only now beginning to explore the properties and biol. importance of ATX as the major LPA-producing phospholipase. In this review, we highlight recent advances in our understanding of the ATX-LPA axis, giving first an update on LPA action and then focusing on ATX, in particular its regulation, its link to cancer and its vital role in vascular development.
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Autotaxin (ATX, also known as Enpp2) is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. Here, we report the crystal structures of mouse ATX alone and in complex with LPAs with different acyl-chain lengths and saturations. These structures reveal that the multidomain architecture helps to maintain the structural rigidity of the lipid-binding pocket, which accommodates the resp. LPA mols. in distinct conformations. They indicate that a loop region in the catalytic domain is a major determinant for the substrate specificity of the Enpp family enzymes. Furthermore, along with biochem. and biol. data, these structures suggest that the produced LPAs are delivered from the active site to cognate G protein-coupled receptors through a hydrophobic channel.
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Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the mol. basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-mol. inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates. We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-mol. therapeutic agents.
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Gijsbers, R.; Ceulemans, H.; Stalmans, W.; Bollen, M. Structural and catalytic similarities between nucleotide pyrophosphatases/phosphodiesterases and alkaline phosphatases J. Biol. Chem. 2001, 276, 1361– 1368
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Zalatan, J.; Fenn, T.; Brunger, A.; Herschlag, D. Structural and functional comparisons of nucleotide pyrophosphatase/phosphodiesterase and alkaline phosphatase: implications for mechanism and evolution Biochemistry 2006, 45, 9788– 9803
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Structural and Functional Comparisons of Nucleotide Pyrophosphatase/Phosphodiesterase and Alkaline Phosphatase: Implications for Mechanism and Evolution
Zalatan, Jesse G.; Fenn, Timothy D.; Brunger, Axel T.; Herschlag, Daniel
Biochemistry (2006), 45 (32), 9788-9803CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
The rapid expansion of the amt. of genomic and structural data has provided many examples of enzymes with evolutionarily related active sites that catalyze different reactions. Functional comparisons of these active sites can provide insight into the origins of the enormous catalytic proficiency of enzymes and the evolutionary changes that can lead to different enzyme activities. The alk. phosphatase (AP) superfamily is an ideal system to use in making such comparisons given the extensive data available on both nonenzymic and enzymic phosphoryl transfer reactions. Some superfamily members, such as AP itself, preferentially hydrolyze phosphate monoesters, whereas others, such as nucleotide pyrophosphatase/phosphodiesterase (NPP), preferentially hydrolyze phosphate diesters. We have measured rate consts. for NPP-catalyzed hydrolysis of phosphate diesters and monoesters. NPP preferentially catalyzes diester hydrolysis by factors of 102-106, depending on the identity of the diester substrate. To identify features of the NPP active site that could lead to preferential phosphate diester hydrolysis, we have detd. the structure of NPP in the absence of ligands and in complexes with vanadate and AMP. Comparisons to existing structures of AP reveal bimetallo cores that are structurally indistinguishable, but there are several distinct structural features outside of the conserved bimetallo site. The structural and functional data together suggest that some of these distinct functional groups provide specific substrate binding interactions, whereas others tune the properties of the bimetallo active site itself to discriminate between phosphate diester and monoester substrates.
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Albers, H.; van Meeteren, L.; Egan, D.; van Tilburg, E.; Moolenaar, W.; Ovaa, H. Discovery and optimization of boronic acid based inhibitors of autotaxin J. Med. Chem. 2010, 53, 4958– 4967
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Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin
Albers, Harald M. H. G.; van Meeteren, Laurens A.; Egan, David A.; van Tilburg, Erica W.; Moolenaar, Wouter H.; Ovaa, Huib
Journal of Medicinal Chemistry (2010), 53 (13), 4958-4967CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) to produce the lipid mediator lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in diverse physiol. and pathol. processes, including vascular development, inflammation, fibrotic disease, and tumor progression. Therefore, targeting ATX with small mol. inhibitors is an attractive therapeutic strategy. We recently reported that 2,4-thiazolidinediones inhibit ATX activity in the micromolar range. Interestingly, inhibitory potency was dramatically increased by introduction of a boronic acid moiety, designed to target the active site threonine in ATX. Here we report on the discovery and further optimization of boronic acid based ATX inhibitors. The most potent of these compds., I, inhibits ATX-mediated LPC hydrolysis in the nanomolar range (IC50 = 6 nM). The finding that ATX can be targeted by boronic acids may aid the development of ATX inhibitors for therapeutic use.
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Albers, H. M.; Dong, A.; van Meeteren, L. A.; Egan, D. A.; Sunkara, M.; van Tilburg, E. W.; Schuurman, K.; van Tellingen, O.; Morris, A. J.; Smyth, S. S.; Moolenaar, W. H.; Ovaa, H. Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 7257– 7262
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Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation
Albers, Harald M. H. G.; Dong, Anping; van Meeteren, Laurens A.; Egan, David A.; Sunkara, Manjula; van Tilburg, Erica W.; Schuurman, Karianne; van Tellingen, Olaf; Morris, Andrew J.; Smyth, Susan S.; Moolenaar, Wouter H.; Ovaa, Huib
Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (16), 7257-7262, S7257/1-S7257/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chem. library, the authors identified thiazolidinediones that selectively inhibit ATX-mediated LPA prodn. both in vitro and in vivo. Inhibitor potency was approx. 100-fold increased (IC50 ∼ 30 nM) after the incorporation of a boronic acid moiety (e.g., compd. I), designed to target the active-site threonine (T210) in ATX. I.v. injection of this inhibitor I into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small mols. hold promise as candidate drugs to target ATX.
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Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds Chem. Rev. 1995, 95, 2457– 2483
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Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds
Miyaura, Norio; Suzuki, Akira
Chemical Reviews (Washington, D. C.) (1995), 95 (7), 2457-83CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review with >250 refs. including title reactions and their mechanisms, prepn. of organoboron reagents, alkoxycarbonylation and dimerization.
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Mizufune, H.; Nakamura, M.; Mitsudera, H. Process research on arylnaphthalene lignan aza-analogues: a new palladium-catalyzed benzannulation of [alpha],[beta]-bisbenzylidenesuccinic acid derivatives Tetrahedron 2006, 62, 8539– 8549
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Cui, P.; Tomsig, J.; McCalmont, W.; Lee, S.; Becker, C.; Lynch, K.; Macdonald, T. Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors Bioorg. Med. Chem. Lett. 2007, 17, 1634– 1640
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Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors
Cui, Peng; Tomsig, Jose L.; McCalmont, William F.; Lee, Sangderk; Becker, Christopher J.; Lynch, Kevin R.; Macdonald, Timothy L.
Bioorganic & Medicinal Chemistry Letters (2007), 17 (6), 1634-1640CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration, and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the prodn. of lysophosphatidic acid (LPA) from lysophophatidylcholine (LPC). ATX is thus an attractive drug target; small mol. inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of β-keto and β-hydroxy phosphonate derivs. of LPA, some of which are potent ATX inhibitors.
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Fischer, G.; Mutel, V.; Trube, G.; Malherbe, P.; Kew, J. N. C.; Mohacsi, E.; Heitz, M. P.; Kemp, J. A. Ro 25–6981, a highly potent and selective blocker of N-methyl-d-aspartate receptors containing the NR2B subunit. characterization in vitro J. Pharmacol. Exp. Therapeutics 1997, 283, 1285– 1292
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Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro
Fischer, G.; Mutel, V.; Trube, G.; Malherbe, P.; Kew, J. N. C.; Mohacsi, E.; Heitz, M. P.; Kemp, J. A.
Journal of Pharmacology and Experimental Therapeutics (1997), 283 (3), 1285-1292CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)
The interaction of Ro 25-6981 with N-methyl-D-aspartate (NMDA) receptors was characterized by a variety of different tests in vitro. Ro 25-6981 inhibited 3H-MK-801 binding to rat forebrain membranes in a biphasic manner with IC50 values of 0.003 μM and 149 μM for high- (about 60%) and low-affinity sites, resp. NMDA receptor subtypes expressed in Xenopus oocytes were blocked with IC50 values of 0.009 μM and 52 μM for the subunit combinations NR1C & NR2B and NR1C & NR2A, resp., which indicated a >5000-fold selectivity. Like ifenprodil, Ro 25-6981 blocked NMDA receptor subtypes in an activity-dependent manner. Ro 25-6981 protected cultured cortical neurons against glutamate toxicity (16 h exposure to 300 μM glutamate) and combined oxygen and glucose deprivation (60 min followed by 20 h recovery) with IC50 values of 0.4 μM and 0.04 μM, resp. Ro 25-6981 was more potent than ifenprodil in all of these tests. It showed no protection against kainate toxicity (exposure to 500 μM for 20 h) and only weak activity in blocking Na+ and Ca2+ channels, activated by exposure of cortical neurons to veratridine (10 μM) and potassium (50 mM), resp. These findings demonstrate that Ro 25-6981 is a highly selective, activity-dependent blocker of NMDA receptors that contain the NR2B subunit.
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Jain, A.; Purohit, C.; Verma, S.; Sankararamakrishnan, R. Close contacts between carbonyl oxygen atoms and aromatic centers in protein structures: π-π or lone-pair-π interactions? J. Phys. Chem. B 2007, 111, 8680– 8683
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Close Contacts between Carbonyl Oxygen Atoms and Aromatic Centers in Protein Structures: π···π or Lone-Pair···π Interactions?
Jain, Alok; Purohit, Chandra Shekhar; Verma, Sandeep; Sankararamakrishnan, Ramasubbu
Journal of Physical Chemistry B (2007), 111 (30), 8680-8683CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
Lone-pair···π and, more recently, π···π interactions have been studied in small mol. crystal structures, and they are the focus of attention in some biomols. In this study, we have systematically analyzed 500 high-resoln. protein structures (resoln. ≤1.8 Å) and identified 286 examples in which carbonyl oxygen atoms approach the arom. centers within a distance of 3.5 Å. Contacts involving backbone carbonyl oxygens are frequently obsd. in helixes and, to some extent, in strands. Geometrical characterization indicates that these contacts have geometry in between that of an ideal π···π and a lone-pair···π interaction. Quantum mech. calcns. using 6-311++G** basis sets reveal that these contacts give rise to energetically favorable interactions and, along with MD simulations, indicate that such interactions could stabilize secondary structures.
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Friesner, R.; Banks, J.; Murphy, R.; Halgren, T.; Klicic, J.; Mainz, D.; Repasky, M.; Knoll, E.; Shelley, M.; Perry, J.; Shaw, D.; Francis, P.; Shenkin, P. Glide: a new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy J. Med. Chem. 2004, 47, 1739– 1749
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Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy
Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.
Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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Friesner, R.; Murphy, R.; Repasky, M.; Frye, L.; Greenwood, J.; Halgren, T.; Sanschagrin, P.; Mainz, D. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes J. Med. Chem. 2006, 49, 6177– 6196
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Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes
Friesner, Richard A.; Murphy, Robert B.; Repasky, Matthew P.; Frye, Leah L.; Greenwood, Jeremy R.; Halgren, Thomas A.; Sanschagrin, Paul C.; Mainz, Daniel T.
Journal of Medicinal Chemistry (2006), 49 (21), 6177-6196CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A novel scoring function to est. protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addn. to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included:(1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce exptl. binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, resp.) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP mol. recognition and water scoring in sepg. active and inactive ligands and avoiding false positives.
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Halgren, T.; Murphy, R.; Friesner, R.; Beard, H.; Frye, L.; Pollard, W. T.; Banks, J. Glide: a new approach for rapid, accurate docking and scoring. 2. enrichment factors in database screening J. Med. Chem. 2004, 47, 1750– 1759
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Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening
Halgren, Thomas A.; Murphy, Robert B.; Friesner, Richard A.; Beard, Hege S.; Frye, Leah L.; Pollard, W. Thomas; Banks, Jay L.
Journal of Medicinal Chemistry (2004), 47 (7), 1750-1759CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Glide's ability to identify active compds. in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of "druglike" decoy ligands that have been selected to be representative of what we believe is likely to be found in the compd. collection of a pharmaceutical or biotechnol. company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that av. measures for both "early" and "global" enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand-protein interactions that violate established principles of phys. chem., particularly as it concerns the exposure to solvent of charged protein and ligand groups. Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers (J. Med. Chem. 2000, 43, 4759-4767) show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
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Tan, S.; Ang, K.; Fong, Y. (Z)- and (E)-5-Arylmethylenehydantoins: spectroscopic properties and configuration assignment J. Chem. Soc., Perkin Trans. 2 1986, 1941– 1944
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(Z)- and (E)-5-(Arylmethylene)hydantoins: spectroscopic properties and configuration assignment
Tan, Sau Fun; Ang, Kok Peng; Fong, Yoke Fan
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1986), (12), 1941-4CODEN: JCPKBH; ISSN:0300-9580.
Both (Z)- and (E)-5-(arylmethylene)-1-methylhydantoins have been obtained directly in substantial proportions from condensations of 1-methylhydantoin with arom. aldehydes. However, the products of similar condensations of hydantoin or 3-methylhydantoins consist almost entirely of the Z-isomers. The configurations of all the 5-(arylmethylene)hydantoins prepd. can be unambiguously assigned by consideration of their 1H and 13C NMR, IR, and UV spectra. The mass spectra of the isomers show similar fragmentation patterns.
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Shelley, J.; Cholleti, A.; Frye, L.; Greenwood, J.; Timlin, M.; Uchimaya, M. Epik: a software program for pKa prediction and protonation state generation for drug-like molecules J. Comput.-Aided Mol. Des. 2007, 21, 681– 691
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Epik: a software program for pKa prediction and protonation state generation for drug-like molecules
Shelley, John C.; Cholleti, Anuradha; Frye, Leah L.; Greenwood, Jeremy R.; Timlin, Mathew R.; Uchimaya, Makoto
Journal of Computer-Aided Molecular Design (2007), 21 (12), 681-691CODEN: JCADEQ; ISSN:0920-654X. (Springer)
Epik is a computer program for predicting pKa values for drug-like mols. Epik can use this capability in combination with technol. for tautomerization to adjust the protonation state of small drug-like mols. to automatically generate one or more of the most probable forms for use in further mol. modeling studies. Many medicinal chems. can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its soly. and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the mol., as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate mols. used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like mols. to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pKa prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the mol. itself rather just for the particular Lewis structure used on input. In addn., a new iterative technol. for generating, ranking and culling the generated protonation states is employed.
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Abstract
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Scheme 1
Scheme 1. Autotaxin (ATX) is Responsible for Hydrolyzing the Lipid Lysophosphatidylcholine (LPC) into Lysophosphatidic Acid (LPA) and Choline
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Figure 1
Figure 1. ATX structure liganded with inhibitor 1 (PDB ID 2XRG). (A) Surface representation of ATX with inhibitor 1 (magenta). (B) Binding of inhibitor 1 to the threonine oxygen nucleophile and two zinc ions. (C) Visualizing the ether linker of inhibitor 1 bound to ATX. (D) Visualizing the degree of freedom for the thiazolidine-2,4-dione core of inhibitor 1 in the ATX binding site.
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Scheme 2
Scheme 2. Synthetic Route Towards Linker Modified Inhibitors
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Scheme 3
Scheme 3. Synthetic Routes Towards Core Modified Inhibitors
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Figure 2
Figure 2. (A) Focus from inside the protein on the thiazolidine-2,4-dione core of inhibitor 1 bound to ATX. (B) Inhibitor 1 docked into the active site of ATX to validate our docking approach. (C) The three best docking poses for the Z-isomer of 28. (D) The three best docking poses for the E-isomer of 28. Docking poses were generated using the docking program Glide.
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References
This article references 24 other publications.
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  Identification of Human Plasma Lysophospholipase D, a Lysophosphatidic Acid-producing Enzyme, as Autotaxin, a Multifunctional Phosphodiesterase
  Tokumura, Akira; Majima, Eiji; Kariya, Yuko; Tominaga, Kyoko; Kogure, Kentaro; Yasuda, Katsuhiko; Fukuzawa, Kenji
  Journal of Biological Chemistry (2002), 277 (42), 39436-39442CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  We purified human plasma lysophospholipase D that produces physiol. active lysophosphatidic acid and showed that it is a sol. form of autotaxin, an ecto-nucleotide pyrophosphatase/phosphodiesterase, originally found as a tumor cell motility-stimulating factor. Its lower Km value for a lysophosphatidylcholine than that for a synthetic substrate of nucleotide suggests that lysophosphatidylcholine is a more likely physiol. substrate for autotaxin and that its predicted physiol. and pathophysiol. functions could be mediated by its activity to produce lysophosphate acid, an intercellular mediator. Recombinant autotaxin was found to have lysophospholipase D activity; its substrate specificity and metal ion requirement were the same as those of the purified plasma enzyme. The activity of lysophospholipase D for exogenous lysophosphatidylcholine in human serum was found to increase in normal pregnant women at the third trimester of pregnancy and to a higher extent in patients in threatened preterm delivery, suggesting its roles in induction of parturition.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnvVeit7k%253D&md5=e9074bb4026cd1349670dafb7e580276
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  Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production
  Umezu-Goto, Makiko; Kishi, Yasuhiro; Taira, Akitsu; Hama, Kotaro; Dohmae, Naoshi; Takio, Koji; Yamori, Takao; Mills, Gordon B.; Inoue, Keizo; Aoki, Junken; Arai, Hiroyuki
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  Autotaxin (ATX) is a tumor cell motility-stimulating factor, originally isolated from melanoma cell supernatants. ATX had been proposed to mediate its effects through 5'-nucleotide pyrophosphatase and phosphodiesterase activities. However, the ATX substrate mediating the increase in cellular motility remains to be identified. Here, we demonstrated that lysophospholipase D (lysoPLD) purified from fetal bovine serum, which catalyzes the prodn. of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC), is identical to ATX. The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate. LPA mediates multiple biol. functions including cytoskeletal reorganization, chemotaxis, and cell growth through activation of specific G protein-coupled receptors. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines. Moreover, we demonstrate that several cancer cell lines release significant amts. of LPC, a substrate for ATX, into the culture medium. The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine prodn. of LPA contributes to tumor cell motility, survival, and proliferation. It also provides potential novel targets for therapy of pathophysiol. states including cancer.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xls1Shsrg%253D&md5=8c091eeb8d9f6da65b0aa75ad7db4011
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  Kanda, H.; Newton, R.; Klein, R.; Morita, Y.; Gunn, M.; Rosen, S. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs Nat. Immunol. 2008, 9, 415– 423
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  Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs
  Kanda, Hidenobu; Newton, Rebecca; Klein, Russell; Morita, Yuka; Gunn, Michael D.; Rosen, Steven D.
  Nature Immunology (2008), 9 (4), 415-423CODEN: NIAMCZ; ISSN:1529-2908. (Nature Publishing Group)
  The extracellular lysophospholipase D autotaxin (ATX) and its product, lysophosphatidic acid, have diverse functions in development and cancer, but little is known about their functions in the immune system. Here we found that ATX had high expression in the high endothelial venules of lymphoid organs and was secreted. Chemokine-activated lymphocytes expressed receptors with enhanced affinity for ATX, which provides a mechanism for targeting the secreted ATX to lymphocytes undergoing recruitment. Lysophosphatidic acid induced chemokinesis in T cells. I.v. injection of enzymically inactive ATX attenuated the homing of T cells to lymphoid tissues, probably through competition with endogenous ATX and exertion of a dominant neg. effect. These results support the idea of a new and general step in the homing cascade in which the ectoenzyme ATX facilitates the entry of lymphocytes into lymphoid organs.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtlGms7c%253D&md5=a9b09e0b4ca5e80504bc2c25162b620e
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  5
  Regulation and biological activities of the autotaxin-LPA axis
  van Meeteren, Laurens A.; Moolenaar, Wouter H.
  Progress in Lipid Research (2007), 46 (2), 145-160CODEN: PLIRDW; ISSN:0163-7827. (Elsevier B.V.)
  A review. Autotaxin (ATX), or nucleotide pyrophosphatase/phosphodiesterase 2 (NPP2), is an exo-enzyme originally identified as a tumor cell autocrine motility factor. ATX is unique among the NPPs in that it primarily functions as a lysophospholipase D, converting lysophosphatidylcholine into the lipid mediator lysophosphatidic acid (LPA). LPA acts on specific G protein-coupled receptors to elicit a wide range of cellular responses, ranging from cell proliferation and migration to neurite remodeling and cytokine prodn. While LPA signaling has been studied extensively over the last decade, we are only now beginning to explore the properties and biol. importance of ATX as the major LPA-producing phospholipase. In this review, we highlight recent advances in our understanding of the ATX-LPA axis, giving first an update on LPA action and then focusing on ATX, in particular its regulation, its link to cancer and its vital role in vascular development.
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6. 6
  Tager, A.; LaCamera, P.; Shea, B.; Campanella, G.; Selman, M.; Zhao, Z.; Polosukhin, V.; Wain, J.; Karimi-Shah, B.; Kim, N.; Hart, W.; Pardo, A.; Blackwell, T.; Xu, Y.; Chun, J.; Luster, A. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak Nat. Med. 2008, 14, 45– 54
  6
  The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak
  Tager, Andrew M.; LaCamera, Peter; Shea, Barry S.; Campanella, Gabriele S.; Selman, Moises; Zhao, Zhenwen; Polosukhin, Vasiliy; Wain, John; Karimi-Shah, Banu A.; Kim, Nancy D.; Hart, William K.; Pardo, Annie; Blackwell, Timothy S.; Xu, Yan; Chun, Jerold; Luster, Andrew D.
  Nature Medicine (New York, NY, United States) (2008), 14 (1), 45-54CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
  Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathol. responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.
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7. 7
  Stefan, C.; Jansen, S.; Bollen, M. Modulation of purinergic signaling by NPP-type ectophosphodiesterases Purinergic. Signal 2006, 2, 361– 370
  There is no corresponding record for this reference.
8. 8
  Nishimasu, H.; Okudaira, S.; Hama, K.; Mihara, E.; Dohmae, N.; Inoue, A.; Ishitani, R.; Takagi, J.; Aoki, J.; Nureki, O. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators Nat. Struct. Mol. Biol. 2011, 18, 205– 212
  8
  Crystal structure of autotaxin and insight into GPCR activation by lipid mediators
  Nishimasu, Hiroshi; Okudaira, Shinichi; Hama, Kotaro; Mihara, Emiko; Dohmae, Naoshi; Inoue, Asuka; Ishitani, Ryuichiro; Takagi, Junichi; Aoki, Junken; Nureki, Osamu
  Nature Structural & Molecular Biology (2011), 18 (2), 205-212CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  Autotaxin (ATX, also known as Enpp2) is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. Here, we report the crystal structures of mouse ATX alone and in complex with LPAs with different acyl-chain lengths and saturations. These structures reveal that the multidomain architecture helps to maintain the structural rigidity of the lipid-binding pocket, which accommodates the resp. LPA mols. in distinct conformations. They indicate that a loop region in the catalytic domain is a major determinant for the substrate specificity of the Enpp family enzymes. Furthermore, along with biochem. and biol. data, these structures suggest that the produced LPAs are delivered from the active site to cognate G protein-coupled receptors through a hydrophobic channel.
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9. 9
  Hausmann, J.; Kamtekar, S.; Christodoulou, E.; Day, J.; Wu, T.; Fulkerson, Z.; Albers, H.; van Meeteren, L.; Houben, A.; van Zeijl, L.; Jansen, S.; Andries, M.; Hall, T.; Pegg, L.; Benson, T.; Kasiem, M.; Harlos, K.; Kooi, C.; Smyth, S.; Ovaa, H.; Bollen, M.; Morris, A.; Moolenaar, W.; Perrakis, A. Structural basis of substrate discrimination and integrin binding by autotaxin Nat. Struct. Mol. Biol. 2011, 18, 198– 204
  9
  Structural basis of substrate discrimination and integrin binding by autotaxin
  Hausmann, Jens; Kamtekar, Satwik; Christodoulou, Evangelos; Day, Jacqueline E.; Wu, Tao; Fulkerson, Zachary; Albers, Harald M. H. G.; van Meeteren, Laurens A.; Houben, Anna J. S.; van Zeijl, Leonie; Jansen, Silvia; Andries, Maria; Hall, Troii; Pegg, Lyle E.; Benson, Timothy E.; Kasiem, Mobien; Harlos, Karl; Vander Kooi, Craig W.; Smyth, Susan S.; Ovaa, Huib; Bollen, Mathieu; Morris, Andrew J.; Moolenaar, Wouter H.; Perrakis, Anastassis
  Nature Structural & Molecular Biology (2011), 18 (2), 198-204CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the mol. basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-mol. inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates. We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-mol. therapeutic agents.
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10. 10
  Gijsbers, R.; Aoki, J.; Arai, H.; Bollen, M. The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site FEBS Lett. 2003, 538, 60– 64
  There is no corresponding record for this reference.
11. 11
  Gijsbers, R.; Ceulemans, H.; Stalmans, W.; Bollen, M. Structural and catalytic similarities between nucleotide pyrophosphatases/phosphodiesterases and alkaline phosphatases J. Biol. Chem. 2001, 276, 1361– 1368
  There is no corresponding record for this reference.
12. 12
  Zalatan, J.; Fenn, T.; Brunger, A.; Herschlag, D. Structural and functional comparisons of nucleotide pyrophosphatase/phosphodiesterase and alkaline phosphatase: implications for mechanism and evolution Biochemistry 2006, 45, 9788– 9803
  12
  Structural and Functional Comparisons of Nucleotide Pyrophosphatase/Phosphodiesterase and Alkaline Phosphatase: Implications for Mechanism and Evolution
  Zalatan, Jesse G.; Fenn, Timothy D.; Brunger, Axel T.; Herschlag, Daniel
  Biochemistry (2006), 45 (32), 9788-9803CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  The rapid expansion of the amt. of genomic and structural data has provided many examples of enzymes with evolutionarily related active sites that catalyze different reactions. Functional comparisons of these active sites can provide insight into the origins of the enormous catalytic proficiency of enzymes and the evolutionary changes that can lead to different enzyme activities. The alk. phosphatase (AP) superfamily is an ideal system to use in making such comparisons given the extensive data available on both nonenzymic and enzymic phosphoryl transfer reactions. Some superfamily members, such as AP itself, preferentially hydrolyze phosphate monoesters, whereas others, such as nucleotide pyrophosphatase/phosphodiesterase (NPP), preferentially hydrolyze phosphate diesters. We have measured rate consts. for NPP-catalyzed hydrolysis of phosphate diesters and monoesters. NPP preferentially catalyzes diester hydrolysis by factors of 102-106, depending on the identity of the diester substrate. To identify features of the NPP active site that could lead to preferential phosphate diester hydrolysis, we have detd. the structure of NPP in the absence of ligands and in complexes with vanadate and AMP. Comparisons to existing structures of AP reveal bimetallo cores that are structurally indistinguishable, but there are several distinct structural features outside of the conserved bimetallo site. The structural and functional data together suggest that some of these distinct functional groups provide specific substrate binding interactions, whereas others tune the properties of the bimetallo active site itself to discriminate between phosphate diester and monoester substrates.
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13. 13
  Albers, H.; van Meeteren, L.; Egan, D.; van Tilburg, E.; Moolenaar, W.; Ovaa, H. Discovery and optimization of boronic acid based inhibitors of autotaxin J. Med. Chem. 2010, 53, 4958– 4967
  13
  Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin
  Albers, Harald M. H. G.; van Meeteren, Laurens A.; Egan, David A.; van Tilburg, Erica W.; Moolenaar, Wouter H.; Ovaa, Huib
  Journal of Medicinal Chemistry (2010), 53 (13), 4958-4967CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) to produce the lipid mediator lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in diverse physiol. and pathol. processes, including vascular development, inflammation, fibrotic disease, and tumor progression. Therefore, targeting ATX with small mol. inhibitors is an attractive therapeutic strategy. We recently reported that 2,4-thiazolidinediones inhibit ATX activity in the micromolar range. Interestingly, inhibitory potency was dramatically increased by introduction of a boronic acid moiety, designed to target the active site threonine in ATX. Here we report on the discovery and further optimization of boronic acid based ATX inhibitors. The most potent of these compds., I, inhibits ATX-mediated LPC hydrolysis in the nanomolar range (IC50 = 6 nM). The finding that ATX can be targeted by boronic acids may aid the development of ATX inhibitors for therapeutic use.
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14. 14
  Albers, H. M.; Dong, A.; van Meeteren, L. A.; Egan, D. A.; Sunkara, M.; van Tilburg, E. W.; Schuurman, K.; van Tellingen, O.; Morris, A. J.; Smyth, S. S.; Moolenaar, W. H.; Ovaa, H. Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 7257– 7262
  14
  Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation
  Albers, Harald M. H. G.; Dong, Anping; van Meeteren, Laurens A.; Egan, David A.; Sunkara, Manjula; van Tilburg, Erica W.; Schuurman, Karianne; van Tellingen, Olaf; Morris, Andrew J.; Smyth, Susan S.; Moolenaar, Wouter H.; Ovaa, Huib
  Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (16), 7257-7262, S7257/1-S7257/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chem. library, the authors identified thiazolidinediones that selectively inhibit ATX-mediated LPA prodn. both in vitro and in vivo. Inhibitor potency was approx. 100-fold increased (IC50 ∼ 30 nM) after the incorporation of a boronic acid moiety (e.g., compd. I), designed to target the active-site threonine (T210) in ATX. I.v. injection of this inhibitor I into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small mols. hold promise as candidate drugs to target ATX.
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15. 15
  Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds Chem. Rev. 1995, 95, 2457– 2483
  15
  Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds
  Miyaura, Norio; Suzuki, Akira
  Chemical Reviews (Washington, D. C.) (1995), 95 (7), 2457-83CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review with >250 refs. including title reactions and their mechanisms, prepn. of organoboron reagents, alkoxycarbonylation and dimerization.
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16. 16
  Mizufune, H.; Nakamura, M.; Mitsudera, H. Process research on arylnaphthalene lignan aza-analogues: a new palladium-catalyzed benzannulation of [alpha],[beta]-bisbenzylidenesuccinic acid derivatives Tetrahedron 2006, 62, 8539– 8549
  There is no corresponding record for this reference.
17. 17
  Cui, P.; Tomsig, J.; McCalmont, W.; Lee, S.; Becker, C.; Lynch, K.; Macdonald, T. Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors Bioorg. Med. Chem. Lett. 2007, 17, 1634– 1640
  17
  Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors
  Cui, Peng; Tomsig, Jose L.; McCalmont, William F.; Lee, Sangderk; Becker, Christopher J.; Lynch, Kevin R.; Macdonald, Timothy L.
  Bioorganic & Medicinal Chemistry Letters (2007), 17 (6), 1634-1640CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
  Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration, and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the prodn. of lysophosphatidic acid (LPA) from lysophophatidylcholine (LPC). ATX is thus an attractive drug target; small mol. inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of β-keto and β-hydroxy phosphonate derivs. of LPA, some of which are potent ATX inhibitors.
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18. 18
  Fischer, G.; Mutel, V.; Trube, G.; Malherbe, P.; Kew, J. N. C.; Mohacsi, E.; Heitz, M. P.; Kemp, J. A. Ro 25–6981, a highly potent and selective blocker of N-methyl-d-aspartate receptors containing the NR2B subunit. characterization in vitro J. Pharmacol. Exp. Therapeutics 1997, 283, 1285– 1292
  18
  Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro
  Fischer, G.; Mutel, V.; Trube, G.; Malherbe, P.; Kew, J. N. C.; Mohacsi, E.; Heitz, M. P.; Kemp, J. A.
  Journal of Pharmacology and Experimental Therapeutics (1997), 283 (3), 1285-1292CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)
  The interaction of Ro 25-6981 with N-methyl-D-aspartate (NMDA) receptors was characterized by a variety of different tests in vitro. Ro 25-6981 inhibited 3H-MK-801 binding to rat forebrain membranes in a biphasic manner with IC50 values of 0.003 μM and 149 μM for high- (about 60%) and low-affinity sites, resp. NMDA receptor subtypes expressed in Xenopus oocytes were blocked with IC50 values of 0.009 μM and 52 μM for the subunit combinations NR1C & NR2B and NR1C & NR2A, resp., which indicated a >5000-fold selectivity. Like ifenprodil, Ro 25-6981 blocked NMDA receptor subtypes in an activity-dependent manner. Ro 25-6981 protected cultured cortical neurons against glutamate toxicity (16 h exposure to 300 μM glutamate) and combined oxygen and glucose deprivation (60 min followed by 20 h recovery) with IC50 values of 0.4 μM and 0.04 μM, resp. Ro 25-6981 was more potent than ifenprodil in all of these tests. It showed no protection against kainate toxicity (exposure to 500 μM for 20 h) and only weak activity in blocking Na+ and Ca2+ channels, activated by exposure of cortical neurons to veratridine (10 μM) and potassium (50 mM), resp. These findings demonstrate that Ro 25-6981 is a highly selective, activity-dependent blocker of NMDA receptors that contain the NR2B subunit.
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19. 19
  Jain, A.; Purohit, C.; Verma, S.; Sankararamakrishnan, R. Close contacts between carbonyl oxygen atoms and aromatic centers in protein structures: π-π or lone-pair-π interactions? J. Phys. Chem. B 2007, 111, 8680– 8683
  19
  Close Contacts between Carbonyl Oxygen Atoms and Aromatic Centers in Protein Structures: π···π or Lone-Pair···π Interactions?
  Jain, Alok; Purohit, Chandra Shekhar; Verma, Sandeep; Sankararamakrishnan, Ramasubbu
  Journal of Physical Chemistry B (2007), 111 (30), 8680-8683CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
  Lone-pair···π and, more recently, π···π interactions have been studied in small mol. crystal structures, and they are the focus of attention in some biomols. In this study, we have systematically analyzed 500 high-resoln. protein structures (resoln. ≤1.8 Å) and identified 286 examples in which carbonyl oxygen atoms approach the arom. centers within a distance of 3.5 Å. Contacts involving backbone carbonyl oxygens are frequently obsd. in helixes and, to some extent, in strands. Geometrical characterization indicates that these contacts have geometry in between that of an ideal π···π and a lone-pair···π interaction. Quantum mech. calcns. using 6-311++G** basis sets reveal that these contacts give rise to energetically favorable interactions and, along with MD simulations, indicate that such interactions could stabilize secondary structures.
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20. 20
  Friesner, R.; Banks, J.; Murphy, R.; Halgren, T.; Klicic, J.; Mainz, D.; Repasky, M.; Knoll, E.; Shelley, M.; Perry, J.; Shaw, D.; Francis, P.; Shenkin, P. Glide: a new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy J. Med. Chem. 2004, 47, 1739– 1749
  20
  Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy
  Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.
  Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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21. 21
  Friesner, R.; Murphy, R.; Repasky, M.; Frye, L.; Greenwood, J.; Halgren, T.; Sanschagrin, P.; Mainz, D. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes J. Med. Chem. 2006, 49, 6177– 6196
  21
  Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes
  Friesner, Richard A.; Murphy, Robert B.; Repasky, Matthew P.; Frye, Leah L.; Greenwood, Jeremy R.; Halgren, Thomas A.; Sanschagrin, Paul C.; Mainz, Daniel T.
  Journal of Medicinal Chemistry (2006), 49 (21), 6177-6196CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A novel scoring function to est. protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addn. to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included:(1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce exptl. binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, resp.) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP mol. recognition and water scoring in sepg. active and inactive ligands and avoiding false positives.
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22. 22
  Halgren, T.; Murphy, R.; Friesner, R.; Beard, H.; Frye, L.; Pollard, W. T.; Banks, J. Glide: a new approach for rapid, accurate docking and scoring. 2. enrichment factors in database screening J. Med. Chem. 2004, 47, 1750– 1759
  22
  Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening
  Halgren, Thomas A.; Murphy, Robert B.; Friesner, Richard A.; Beard, Hege S.; Frye, Leah L.; Pollard, W. Thomas; Banks, Jay L.
  Journal of Medicinal Chemistry (2004), 47 (7), 1750-1759CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Glide's ability to identify active compds. in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of "druglike" decoy ligands that have been selected to be representative of what we believe is likely to be found in the compd. collection of a pharmaceutical or biotechnol. company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that av. measures for both "early" and "global" enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand-protein interactions that violate established principles of phys. chem., particularly as it concerns the exposure to solvent of charged protein and ligand groups. Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers (J. Med. Chem. 2000, 43, 4759-4767) show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
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23. 23
  Tan, S.; Ang, K.; Fong, Y. (Z)- and (E)-5-Arylmethylenehydantoins: spectroscopic properties and configuration assignment J. Chem. Soc., Perkin Trans. 2 1986, 1941– 1944
  23
  (Z)- and (E)-5-(Arylmethylene)hydantoins: spectroscopic properties and configuration assignment
  Tan, Sau Fun; Ang, Kok Peng; Fong, Yoke Fan
  Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1986), (12), 1941-4CODEN: JCPKBH; ISSN:0300-9580.
  Both (Z)- and (E)-5-(arylmethylene)-1-methylhydantoins have been obtained directly in substantial proportions from condensations of 1-methylhydantoin with arom. aldehydes. However, the products of similar condensations of hydantoin or 3-methylhydantoins consist almost entirely of the Z-isomers. The configurations of all the 5-(arylmethylene)hydantoins prepd. can be unambiguously assigned by consideration of their 1H and 13C NMR, IR, and UV spectra. The mass spectra of the isomers show similar fragmentation patterns.
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24. 24
  Shelley, J.; Cholleti, A.; Frye, L.; Greenwood, J.; Timlin, M.; Uchimaya, M. Epik: a software program for pKa prediction and protonation state generation for drug-like molecules J. Comput.-Aided Mol. Des. 2007, 21, 681– 691
  24
  Epik: a software program for pKa prediction and protonation state generation for drug-like molecules
  Shelley, John C.; Cholleti, Anuradha; Frye, Leah L.; Greenwood, Jeremy R.; Timlin, Mathew R.; Uchimaya, Makoto
  Journal of Computer-Aided Molecular Design (2007), 21 (12), 681-691CODEN: JCADEQ; ISSN:0920-654X. (Springer)
  Epik is a computer program for predicting pKa values for drug-like mols. Epik can use this capability in combination with technol. for tautomerization to adjust the protonation state of small drug-like mols. to automatically generate one or more of the most probable forms for use in further mol. modeling studies. Many medicinal chems. can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its soly. and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the mol., as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate mols. used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like mols. to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pKa prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the mol. itself rather just for the particular Lewis structure used on input. In addn., a new iterative technol. for generating, ranking and culling the generated protonation states is employed.
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- PDB: 2XRG
Supporting Information
Supporting Information
Contains Michael acceptor study of inhibitor 1, dose–response curves of inhibitors 17, 19, and 36, image visualizing π-stacking of carbonyl inhibitor 1 with ATX residue F274, image of docked and X-ray pose of inhibitor 1 superimposed, experimental details of compounds 13–20, 26, and E-28, details on the syntheses of aldehydes 2–6 and amine linker-based inhibitor 36, and spectral data of all intermediates and target molecules. This material is available free of charge via the Internet at http://pubs.acs.org.
- jm200310q_si_001.pdf (6.6 MB)
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Structure-Based Design of Novel Boronic Acid-Based Inhibitors of AutotaxinClick to copy article linkArticle link copied!

Journal of Medicinal Chemistry

Abstract

† Author-Status

Introduction

Scheme 1

Figure 1

Results and Discussion

Design of Inhibitors

Chemical Synthesis of Modified Inhibitors

Scheme 2

Scheme 3

Structure–Activity Relations of Inhibitors and Autotaxin

Figure 2

Experimental Section

Chemistry

General Procedure for Borylation of Aldehydes and Pinacol Deprotection (12–16)

(4-((4-Formylphenoxy)methyl)phenyl)boronic Acid (12)

General Method for Knoevenagel Condensation (1, 17–20, 26, and E-28)

(Z)-4-[(4-{[3-(4-Fluorobenzyl)-2,4-dioxo-1,3-thiazolan-5-yliden]methyl}phenoxy) methyl]benzene Boronic Acid (1)

(4-((4-((3-(4-Fluorobenzyl)-2,4-dioxothiazolidin-5-yl)methyl)phenoxy)methyl) phenyl)boronic Acid (21)

(4-((4-((3-(4-Fluorobenzyl)-4-hydroxy-2-oxothiazolidin-5-yl)methyl)phenoxy) methyl)phenyl)boronic Acid (22)

(4-((4-((3-(4-Fluorobenzyl)-2-oxo-2,3-dihydrothiazol-5-yl)methyl)phenoxy) methyl)phenyl)boronic Acid (23)

3-(4-Fluorobenzyl)imidazolidine-2,4-dione (25)

3-(4-Fluorobenzyl)-1-methylimidazolidine-2,4-dione (27)

(Z)-(4-((4-((1-(4-Fluorobenzyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl) phenoxy)methyl)phenyl)boronic Acid (Z-28)

(E)-(4-((4-((2,5-Dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl)boronic Acid (31)

(E)-(4-((4-((1-(4-Fluorobenzyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy) methyl)phenyl)boronic Acid (32)

(S)-2-(4-Fluorobenzyl)-7-hydroxy-10,10a-dihydroimidazo[1,5-b]isoquinoline-1,3(2H,5H)-dione (S-34)

(R)-2-(4-Fluorobenzyl)-7-hydroxy-10,10a-dihydroimidazo[1,5-b]isoquinoline-1,3(2H,5H)-dione (R-34)

(S)-(4-(((2-(4-Fluorobenzyl)-1,3-dioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolin-7-yl)oxy)methyl)phenyl)boronic Acid (S-35)

(R)-(4-(((2-(4-Fluorobenzyl)-1,3-dioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolin-7-yl)oxy)methyl)phenyl)boronic acid (R-35)

Choline Release Assay. (13)

Docking Experiments, Protein, and Ligand Preparation

Supporting Information

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Acknowledgment

Non-Standard Abbreviations

References

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Journal of Medicinal Chemistry

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Abstract

Scheme 1

Figure 1

Scheme 2

Scheme 3

Figure 2

References

Supporting Information

Supporting Information

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Structure-Based Design of Novel Boronic Acid-Based Inhibitors of Autotaxin
Click to copy article linkArticle link copied!