Characterization of 2,4-Dianilinopyrimidines Against Five P. falciparum Kinases PfARK1, PfARK3, PfNEK3, PfPK9, and PfPKB

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This article references 47 other publications.

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   World Malaria Report 2022; World Health Organization: Geneva, 2022.

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   Brown, J. R.; Drewry, D.; Gamo, F.-J.; Garcia-Bustos, J. F. Kinase Inhibitors Among Hits from Malaria Cellular Screens. In Protein Phosphorylation in Parasites; Wiley-VCH: Weinheim, Germany, 2013; pp 261– 291.

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   Lucet, I. S.; Tobin, A.; Drewry, D.; Wilks, A. F.; Doerig, C. Plasmodium Kinases as Targets for New-Generation Antimalarials. Future Med. Chem. 2012, 4, 2295– 2310,  DOI: 10.4155/fmc.12.183

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   Plasmodium kinases as targets for new-generation antimalarials

   Lucet, Isabelle S.; Tobin, Andrew; Drewry, David; Wilks, Andrew F.; Doerig, Christian

   Future Medicinal Chemistry (2012), 4 (18), 2295-2310CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)

   A review. There is an urgent need for the development of new antimalarial drugs with novel modes of actions. The malarial parasite, Plasmodium falciparum, has a relatively small kinome of <100 kinases, with many members exhibiting a high degree of structural divergence from their host counterparts. A no. of Plasmodium kinases have recently been shown by reverse genetics to be essential for various parts of the complex parasitic life cycle, and are thus genetically validated as potential targets. Implementation of mass spectrometry-based phosphoproteomics approaches has informed on key phospho-signalling pathways in the parasite. In addn., global phenotypic screens have revealed a large no. of putative protein kinase inhibitors with antimalarial potency. Taken together, these investigations point to the Plasmodium kinome as a rich source of potential new targets. In this review, we highlight recent progress made towards this goal.

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   Arendse, L. B.; Wyllie, S.; Chibale, K.; Gilbert, I. H. Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities. ACS Infect. Dis. 2021, 7, 518– 534,  DOI: 10.1021/acsinfecdis.0c00724

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   Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities

   Arendse, Lauren B.; Wyllie, Susan; Chibale, Kelly; Gilbert, Ian H.

   ACS Infectious Diseases (2021), 7 (3), 518-534CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)

   A review. Protein and phosphoinositide kinases have been successfully exploited as drug targets in various disease areas, principally in oncol. In malaria, several protein kinases are under investigation as potential drug targets, and an inhibitor of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4KIIIβ) is currently in phase 2 clin. studies. In this Perspective, we review the potential of kinases as drug targets for the treatment of malaria. Kinases are known to be readily druggable, and many are essential for parasite survival. A key challenge in the design of Plasmodium kinase inhibitors is obtaining selectivity over the corresponding human ortholog(s) and other human kinases due to the highly conserved nature of the shared ATP binding site. Notwithstanding this, there are some notable differences between the Plasmodium and human kinome that may be exploitable. There is also the potential for designed polypharmacol., where several Plasmodium kinases are inhibited by the same drug. Prior to starting the drug discovery process, it is important to carefully assess potential kinase targets to ensure that the inhibition of the desired kinase will kill the parasites in the required life-cycle stages with a sufficiently fast rate of kill. Here, we highlight key target attributes and exptl. approaches to consider and summarize the progress that has been made targeting Plasmodium PI4KIIIβ, cGMP-dependent protein kinase, and cyclin-dependent-like kinase 3.

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   Ong, H. W.; Adderley, J.; Tobin, A. B.; Drewry, D. H.; Doerig, C. Parasite and Host Kinases as Targets for Antimalarials. Expert Opin. Ther. Targets 2023, 27, 151– 169,  DOI: 10.1080/14728222.2023.2185511

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   Parasite and host kinases as targets for antimalarials

   Ong, Han Wee; Adderley, Jack; Tobin, Andrew B.; Drewry, David H.; Doerig, Christian

   Expert Opinion on Therapeutic Targets (2023), 27 (2), 151-169CODEN: EOTTAO; ISSN:1472-8222. (Taylor & Francis Ltd.)

   A review. The deployment of Artemisinin-based combination therapies and transmission control measures led to a decrease in the global malaria burden over the recent decades. Unfortunately, this trend is now reversing, in part due to resistance against available treatments, calling for the development of new drugs against untapped targets to prevent cross-resistance. In view of their demonstrated druggability in noninfectious diseases, protein kinases represent attractive targets. Kinase-focussed antimalarial drug discovery is facilitated by the availability of kinase-targeting scaffolds and large libraries of inhibitors, as well as high-throughput phenotypic and biochem. assays. We present an overview of validated Plasmodium kinase targets and their inhibitors, and briefly discuss the potential of host cell kinases as targets for host-directed therapy. We propose priority research areas, including (i) diversification of Plasmodium kinase targets (at present most efforts focus on a very small no. of targets); (ii) polypharmacol. as an avenue to limit resistance (kinase inhibitors are highly suitable in this respect); and (iii) preemptive limitation of resistance through host-directed therapy (targeting host cell kinases that are required for parasite survival) and transmission-blocking through targeting sexual stage-specific kinases as a strategy to protect curative drugs from the spread of resistance.

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   Ward, P.; Equinet, L.; Packer, J.; Doerig, C. Protein Kinases of the Human Malaria Parasite Plasmodium Falciparum: The Kinome of a Divergent Eukaryote. BMC Genomics 2004, 5, 79,  DOI: 10.1186/1471-2164-5-79

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   Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote

   Ward Pauline; Equinet Leila; Packer Jeremy; Doerig Christian

   BMC genomics (2004), 5 (), 79 ISSN:.

   BACKGROUND: Malaria, caused by the parasitic protist Plasmodium falciparum, represents a major public health problem in the developing world. The P. falciparum genome has been sequenced, which provides new opportunities for the identification of novel drug targets. Eukaryotic protein kinases (ePKs) form a large family of enzymes with crucial roles in most cellular processes; hence malarial ePKS represent potential drug targets. We report an exhaustive analysis of the P. falciparum genomic database (PlasmoDB) aimed at identifying and classifying all ePKs in this organism. RESULTS: Using a variety of bioinformatics tools, we identified 65 malarial ePK sequences and constructed a phylogenetic tree to position these sequences relative to the seven established ePK groups. Predominant features of the tree were: (i) that several malarial sequences did not cluster within any of the known ePK groups; (ii) that the CMGC group, whose members are usually involved in the control of cell proliferation, had the highest number of malarial ePKs; and (iii) that no malarial ePK clustered with the tyrosine kinase (TyrK) or STE groups, pointing to the absence of three-component MAPK modules in the parasite. A novel family of 20 ePK-related sequences was identified and called FIKK, on the basis of a conserved amino acid motif. The FIKK family seems restricted to Apicomplexa, with 20 members in P. falciparum and just one member in some other Apicomplexan species. CONCLUSION: The considerable phylogenetic distance between Apicomplexa and other Eukaryotes is reflected by profound divergences between the kinome of malaria parasites and that of yeast or mammalian cells.

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   Anamika; Srinivasan, N.; Krupa, A. A Genomic Perspective of Protein Kinases in Plasmodium Falciparum. Proteins Struct. Funct. Bioinforma. 2005, 58, 180– 189,  DOI: 10.1002/prot.20278

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   A genomic perspective of protein kinases in Plasmodium falciparum

   Anamika; Srinivasan N; Krupa A

   Proteins (2005), 58 (1), 180-9 ISSN:.

   Protein kinases are central to regulation of cellular signaling in the eukaryotes. Well-conserved and lineage-specific protein kinases have previously been identified from various completely sequenced genomes of eukaryotes. The current work describes a genome-wide analysis for protein kinases encoded in the Plasmodium falciparum genome. Using a few different profile matching methods, we have identified 99 protein kinases or related proteins in the parasite genome. We have classified these kinases into subfamilies and analyzed them in the context of noncatalytic domains that occur in these catalytic kinase domain-containing proteins. Compared to most eukaryotic protein kinases, these sequences vary significantly in terms of their lengths, inserts in catalytic domains, and co-occurring domains. Catalytic and noncatalytic domains contain long stretches of repeats of positively charged and other polar amino acids. Various components of the cell cycle, including 4 cyclin-dependent kinase (CDK) homologues, 2 cyclins, 1 CDK regulatory subunit, and 1 kinase-associated phosphatase, are identified. Identification of putative mitogen-activated protein (MAP) Kinase and MAP Kinase Kinase of P. falciparum suggests a new paradigm in the highly conserved signaling pathway of eukaryotes. The calcium-dependent kinase family, well represented in P. falciparum, shows varying domain combinations with EF-hands and pleckstrin homology domains. The analysis reveals a new subfamily of protein kinases having limited sequence similarity with previously known subfamilies. A new transmembrane kinase with 6 membrane-spanning regions is identified. Putative apicoplast targeting sequences have been detected in some of these protein kinases, suggesting their export to the apicoplast.

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   Solyakov, L.; Halbert, J.; Alam, M. M.; Semblat, J.-P.; Dorin-Semblat, D.; Reininger, L.; Bottrill, A. R.; Mistry, S.; Abdi, A.; Fennell, C.; Holland, Z.; Demarta, C.; Bouza, Y.; Sicard, A.; Nivez, M.-P.; Eschenlauer, S.; Lama, T.; Thomas, D. C.; Sharma, P.; Agarwal, S.; Kern, S.; Pradel, G.; Graciotti, M.; Tobin, A. B.; Doerig, C. Global Kinomic and Phospho-Proteomic Analyses of the Human Malaria Parasite Plasmodium Falciparum. Nat. Commun. 2011, 2, 565,  DOI: 10.1038/ncomms1558

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   Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum

   Solyakov Lev; Halbert Jean; Alam Mahmood M; Semblat Jean-Philippe; Dorin-Semblat Dominique; Reininger Luc; Bottrill Andrew R; Mistry Sharad; Abdi Abdirhaman; Fennell Clare; Holland Zoe; Demarta Claudia; Bouza Yvan; Sicard Audrey; Nivez Marie-Paule; Eschenlauer Sylvain; Lama Tenzing; Thomas Divya Catherine; Sharma Pushkar; Agarwal Shruti; Kern Selina; Pradel Gabriele; Graciotti Michele; Tobin Andrew B; Doerig Christian

   Nature communications (2011), 2 (), 565 ISSN:.

   The role of protein phosphorylation in the life cycle of malaria parasites is slowly emerging. Here we combine global phospho-proteomic analysis with kinome-wide reverse genetics to assess the importance of protein phosphorylation in Plasmodium falciparum asexual proliferation. We identify 1177 phosphorylation sites on 650 parasite proteins that are involved in a wide range of general cellular activities such as DNA synthesis, transcription and metabolism as well as key parasite processes such as invasion and cyto-adherence. Several parasite protein kinases are themselves phosphorylated on putative regulatory residues, including tyrosines in the activation loop of PfGSK3 and PfCLK3; we show that phosphorylation of PfCLK3 Y526 is essential for full kinase activity. A kinome-wide reverse genetics strategy identified 36 parasite kinases as likely essential for erythrocytic schizogony. These studies not only reveal processes that are regulated by protein phosphorylation, but also define potential anti-malarial drug targets within the parasite kinome.

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9. 9

   Zhang, M.; Wang, C.; Otto, T. D.; Oberstaller, J.; Liao, X.; Adapa, S. R.; Udenze, K.; Bronner, I. F.; Casandra, D.; Mayho, M.; Brown, J.; Li, S.; Swanson, J.; Rayner, J. C.; Jiang, R. H. Y.; Adams, J. H. Uncovering the Essential Genes of the Human Malaria Parasite Plasmodium Falciparum by Saturation Mutagenesis. Science 2018, 360, eaap7847  DOI: 10.1126/science.aap7847

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10. 10

    Xing, L.; Rai, B.; Lunney, E. A. Scaffold Mining of Kinase Hinge Binders in Crystal Structure Database. J. Comput. Aided. Mol. Des. 2014, 28, 13– 23,  DOI: 10.1007/s10822-013-9700-4

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    10

    Scaffold mining of kinase hinge binders in crystal structure database

    Xing, Li; Rai, Brajesh; Lunney, Elizabeth A.

    Journal of Computer-Aided Molecular Design (2014), 28 (1), 13-23CODEN: JCADEQ; ISSN:0920-654X. (Springer)

    Protein kinases are the second most prominent group of drug targets, after G-protein-coupled receptors. Despite their distinct inhibition mechanisms, the majority of kinase inhibitors engage the conserved hydrogen bond interactions with the backbone of hinge residues. The authors mined Pfizer internal crystal structure database (CSDb) comprising of several thousand of public as well as internal x-ray binary complexes to compile an inclusive list of hinge binding scaffolds. The min. ring scaffolds with directly attached hetero-atoms and functional groups were extd. from the full compds. by applying a rule-based filtering procedure employing a comprehensive annotation of ATP-binding site of the human kinase complements. The results indicated large no. of kinase inhibitors of diverse chem. structures are derived from a relatively small no. of common scaffolds, which serve as the crit. recognition elements for protein kinase interaction. Out of the nearly 4,000 kinase-inhibitor complexes in the CSDb the authors identified approx. 600 unique scaffolds. Hinge scaffolds are overwhelmingly flat with very little sp3 characteristics, and are less lipophilic than their corresponding parent compds. Examples of the most common as well as the uncommon hinge scaffolds are presented. Although the most common scaffolds are found in complex with multiple kinase targets, a large no. of them are uniquely bound to a specific kinase, suggesting certain scaffolds could be more promiscuous than the others. The compiled collection of hinge scaffolds along with their three-dimensional binding coordinates could serve as basis set for hinge hopping, a practice frequently employed to generate novel invention as well as to optimize existing leads in medicinal chem.

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    Xing, L.; Klug-Mcleod, J.; Rai, B.; Lunney, E. A. Kinase Hinge Binding Scaffolds and Their Hydrogen Bond Patterns. Bioorg. Med. Chem. 2015, 23, 6520– 6527,  DOI: 10.1016/j.bmc.2015.08.006

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    11

    Kinase hinge binding scaffolds and their hydrogen bond patterns

    Xing, Li; Klug-Mcleod, Jacquelyn; Rai, Brajesh; Lunney, Elizabeth A.

    Bioorganic & Medicinal Chemistry (2015), 23 (19), 6520-6527CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    Protein kinases constitute a major class of intracellular signaling mols., and describe some of the most prominent drug targets. Kinase inhibitors commonly employ small chem. scaffolds that form hydrogen bonds with the kinase hinge residues connecting the N- and C-terminal lobes of the catalytic domain. In general the satisfied hydrogen bonds are required for potent inhibition, therefore constituting a conserved feature in the majority of inhibitor-kinase interactions. From systematically analyzing the kinase scaffolds extd. from Pfizer crystal structure database (CSDb) the authors recognize that large no. of kinase inhibitors of diverse chem. structures are derived from a relatively small no. of common scaffolds. Depending on specific substitution patterns, scaffolds may demonstrate versatile binding capacities to interact with kinase hinge. Afforded by thousands of ligand-protein binary complexes, the hinge hydrogen bond patterns were analyzed with a focus on their three-dimensional configurations. Most of the compds. engage H6 NH for hinge recognition. Dual hydrogen bonds are commonly obsd. with addnl. recruitment of H4 CO upstream and/or H6 CO downstream. Triple hydrogen bonds accounts for small no. of binary complexes. An unusual hydrogen bond with a non-canonical H5 conformation is obsd., requiring a peptide bond flip by a glycine residue at the H6 position. Addnl. hydrogen bonds to kinase hinge do not necessarily correlate with an increase in potency; conversely they appear to compromise kinase selectivity. Such learnings could enhance the prospect of successful therapy design.

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    Gamo, F.-J.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J.-L.; Vanderwall, D. E.; Green, D. V. S.; Kumar, V.; Hasan, S.; Brown, J. R.; Peishoff, C. E.; Cardon, L. R.; Garcia-Bustos, J. F. Thousands of Chemical Starting Points for Antimalarial Lead Identification. Nature 2010, 465, 305– 310,  DOI: 10.1038/nature09107

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    Thousands of chemical starting points for antimalarial lead identification

    Gamo, Francisco-Javier; Sanz, Laura M.; Vidal, Jaume; de Cozar, Cristina; Alvarez, Emilio; Lavandera, Jose-Luis; Vanderwall, Dana E.; Green, Darren V. S.; Kumar, Vinod; Hasan, Samiul; Brown, James R.; Peishoff, Catherine E.; Cardon, Lon R.; Garcia-Bustos, Jose F.

    Nature (London, United Kingdom) (2010), 465 (7296), 305-310CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

    Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chem. class of antimalarials has been introduced into clin. practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compds. in GlaxoSmithKline's chem. library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 μM concn. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compds. originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chem. structures and assocd. data are hereby made public to encourage addnl. drug lead identification efforts and further research into this disease.

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    Crowther, G. J.; Hillesland, H. K.; Keyloun, K. R.; Reid, M. C.; Lafuente-Monasterio, M. J.; Ghidelli-Disse, S.; Leonard, S. E.; He, P.; Jones, J. C.; Krahn, M. M.; Mo, J. S.; Dasari, K. S.; Fox, A. M. W.; Boesche, M.; El Bakkouri, M.; Rivas, K. L.; Leroy, D.; Hui, R.; Drewes, G.; Maly, D. J.; Van Voorhis, W. C.; Ojo, K. K. Biochemical Screening of Five Protein Kinases from Plasmodium Falciparum against 14,000 Cell-Active Compounds. PLoS One 2016, 11, e0149996  DOI: 10.1371/journal.pone.0149996

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    13

    Biochemical screening of five protein kinases from Plasmodium falciparum against 14,000 cell-active compounds

    Crowther, Gregory J.; Hillesland, Heidi K.; Keyloun, Katelyn R.; Reid, Molly C.; Lafuente-Monasterio, Maria Jose; Ghidelli-Disse, Sonja; Leonard, Stephen E.; He, Panqing; Jones, Jackson C.; Krahn, Mallory M.; Mo, Jack S.; Dasari, Kartheek S.; Fox, Anna M. W.; Boesche, Markus; El Bakkouri, Majida; Rivas, Kasey L.; Leroy, Didier; Hui, Raymond; Drewes, Gerard; Maly, Dustin J.; Van Voorhis, Wesley C.; Ojo, Kayode K.

    PLoS One (2016), 11 (3), e0149996/1-e0149996/16CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

    In 2010 the identities of thousands of anti-Plasmodium compds. were released publicly to facilitate malaria drug development. Understanding these compds. mechanisms of action, i.e., the specific mol. targets by which they kill the parasite, would further facilitate the drug development process. Given that kinases are promising anti-malaria targets, the authors screened ∼14,000 cell-active compds. for activity against five different protein kinases. Collections of cell-active compds. from GlaxoSmithKline (the ∼13,000-compd. Tres Cantos Antimalarial Set, or TCAMS), St. Jude Children's Research Hospital (260 compds.), and the Medicines for Malaria Venture (the 400-compd. Malaria Box) were screened in biochem. assays of Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-assocd. protein kinase 2 (MAPK2/ MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC50 < 1 μM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Addnl., kinome-wide competition assays revealed a compd. that inhibits CDPK4 with few effects on ∼150 human kinases, and several related compds. that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. The authors' data suggest that inhibiting multiple Plasmodium kinase targets without harming human cells is challenging but feasible.

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    Phuangsawai, O.; Beswick, P.; Ratanabunyong, S.; Tabtimmai, L.; Suphakun, P.; Obounchoey, P.; Srisook, P.; Horata, N.; Chuckowree, I.; Hannongbua, S.; Ward, S. E.; Choowongkomon, K.; Gleeson, M. P. Evaluation of the Anti-Malarial Activity and Cytotoxicity of 2,4-Diamino-Pyrimidine-Based Kinase Inhibitors. Eur. J. Med. Chem. 2016, 124, 896– 905,  DOI: 10.1016/j.ejmech.2016.08.055

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    14

    Evaluation of the anti-malarial activity and cytotoxicity of 2,4-diamino-pyrimidine-based kinase inhibitors

    Phuangsawai, Oraphan; Beswick, Paul; Ratanabunyong, Siriluk; Tabtimmai, Lueacha; Suphakun, Praphasri; Obounchoey, Phongphat; Srisook, Pimonwan; Horata, Natharinee; Chuckowree, Irina; Hannongbua, Supa; Ward, Simon E.; Choowongkomon, Kiattawee; Gleeson, M. Paul

    European Journal of Medicinal Chemistry (2016), 124 (), 896-905CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    A series of 2,4 diamino-pyrimidines have been identified from an anal. of open access high throughput antimalarial screening data reported by GlaxoSmithKline at the 3D7 and resistant Dd2 strains. SAR expansion has been performed using structural knowledge of the most plausible parasite target. Seventeen new analogs have been synthesized and tested against the resistant K1 strain of Plasmodium falciparum (Pf). The cytotoxicity of the compds. was assessed in Vero and A549 cells and their selectivity towards human kinases including JAK2 and EGFR were undertaken. The authors identified 2 compds. as sub-micromolar inhibitors, with equiv. antimalarial activity to Chloroquine (CQ). Compds. I and II, μM inhibitors of Pf, displayed improved cytotoxicity with weak inhibition of the human kinases.

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    Toviwek, B.; Phuangsawai, O.; Konsue, A.; Hannongbua, S.; Riley, J.; Mutter, N.; Anderson, M.; Webster, L.; Hallyburton, I.; Read, K. D.; Gleeson, M. P. Preparation, Biological & Cheminformatics-Based Assessment of N2,N4-Diphenylpyrimidine-2,4-Diamine as Potential Kinase-Targeted Antimalarials. Bioorg. Med. Chem. 2021, 46, 116348,  DOI: 10.1016/j.bmc.2021.116348

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    15

    Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials

    Toviwek, Borvornwat; Phuangsawai, Oraphan; Konsue, Adchatawut; Hannongbua, Supa; Riley, Jennifer; Mutter, Nicole; Anderson, Mark; Webster, Lauren; Hallyburton, Irene; Read, Kevin D.; Gleeson, M. Paul

    Bioorganic & Medicinal Chemistry (2021), 46 (), 116348CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepd. in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and soly. of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compds. against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, soly., permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66μM at the 3D7 strain and a selectivity (SI) of ∼ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low exptl. logD7.4 (2.27), reasonable soly. (124μg/mL), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homol. modeling and mol. docking were used to evaluate whether compds. could indeed bind to these targets with valid binding modes. In vitro biol. testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

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    Bohmer, M. J.; Wang, J.; Istvan, E. S.; Luth, M. R.; Collins, J. E.; Huttlin, E. L.; Wang, L.; Mittal, N.; Hao, M.; Kwiatkowski, N. P.; Gygi, S. P.; Chakrabarti, R.; Deng, X.; Goldberg, D. E.; Winzeler, E. A.; Gray, N. S.; Chakrabarti, D. Human Polo-like Kinase Inhibitors as Antiplasmodials. ACS Infect. Dis. 2023, 9, 1004– 1021,  DOI: 10.1021/acsinfecdis.3c00025

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    16

    Human Polo-like Kinase Inhibitors as Antiplasmodials

    Bohmer, Monica J.; Wang, Jinhua; Istvan, Eva S.; Luth, Madeline R.; Collins, Jennifer E.; Huttlin, Edward L.; Wang, Lushun; Mittal, Nimisha; Hao, Mingfeng; Kwiatkowski, Nicholas P.; Gygi, Steven P.; Chakrabarti, Ratna; Deng, Xianming; Goldberg, Daniel E.; Winzeler, Elizabeth A.; Gray, Nathanael S.; Chakrabarti, Debopam

    ACS Infectious Diseases (2023), 9 (4), 1004-1021CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)

    Protein kinases have proven to be a very productive class of therapeutic targets, and over 90 inhibitors are currently in clin. use primarily for the treatment of cancer. Repurposing these inhibitors as antimalarials could provide an accelerated path to drug development. In this study, we identified BI-2536 (compd. 1), a known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening of addnl. PLK1 inhibitors revealed further antiplasmodial candidates despite the lack of an obvious orthologue of PLKs in Plasmodium. A subset of these inhibitors was profiled for their in vitro killing profile, and commonalities between the killing rate and inhibition of nuclear replication were noted. A kinase panel screen identified PfNEK3 as a shared target of these PLK1 inhibitors; however, phosphoproteome anal. confirmed distinct signaling pathways were disrupted by two structurally distinct inhibitors, suggesting PfNEK3 may not be the sole target. Genomic anal. of BI-2536-resistant parasites revealed mutations in genes assocd. with the starvation-induced stress response, suggesting BI-2536 may also inhibit an aminoacyl-tRNA synthetase.

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17. 17

    Ramsden, N.; Perrin, J.; Ren, Z.; Lee, B. D.; Zinn, N.; Dawson, V. L.; Tam, D.; Bova, M.; Lang, M.; Drewes, G.; Bantscheff, M.; Bard, F.; Dawson, T. M.; Hopf, C. Chemoproteomics-Based Design of Potent LRRK2-Selective Lead Compounds That Attenuate Parkinson’s Disease-Related Toxicity in Human Neurons. ACS Chem. Biol. 2011, 6, 1021– 1028,  DOI: 10.1021/cb2002413

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    17

    Chemoproteomics-Based Design of Potent LRRK2-Selective Lead Compounds That Attenuate Parkinson's Disease-Related Toxicity in Human Neurons

    Ramsden, Nigel; Perrin, Jessica; Ren, Zhao; Lee, Byoung Dae; Zinn, Nico; Dawson, Valina L.; Tam, Danny; Bova, Michael; Lang, Manja; Drewes, Gerard; Bantscheff, Marcus; Bard, Frederique; Dawson, Ted M.; Hopf, Carsten

    ACS Chemical Biology (2011), 6 (10), 1021-1028CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)

    Leucine-rich repeat kinase-2 (LRRK2) mutations are the most important cause of familial Parkinson's disease, and non-selective inhibitors are protective in rodent disease models. Because of their poor potency and selectivity, the neuroprotective mechanism of these tool compds. has remained elusive so far, and it is still unknown whether selective LRRK2 inhibition can attenuate mutant LRRK2-dependent toxicity in human neurons. Here, we employ a chemoproteomics strategy to identify potent, selective, and metabolically stable LRRK2 inhibitors. We demonstrate that CZC-25146 (I) prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency. These precise chem. probes further validate this emerging therapeutic strategy. They will enable more detailed studies of LRRK2-dependent signaling and pathogenesis and accelerate drug discovery.

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18. 18

    Jester, B. W.; Cox, K. J.; Gaj, A.; Shomin, C. D.; Porter, J. R.; Ghosh, I. A Coiled-Coil Enabled Split-Luciferase Three-Hybrid System: Applied Toward Profiling Inhibitors of Protein Kinases. J. Am. Chem. Soc. 2010, 132, 11727– 11735,  DOI: 10.1021/ja104491h

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    18

    A Coiled-Coil Enabled Split-Luciferase Three-Hybrid System: Applied Toward Profiling Inhibitors of Protein Kinases

    Jester, Benjamin W.; Cox, Kurt J.; Gaj, Alicia; Shomin, Carolyn D.; Porter, Jason R.; Ghosh, Indraneel

    Journal of the American Chemical Society (2010), 132 (33), 11727-11735CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    The 518 protein kinases encoded in the human genome are exquisitely regulated and their aberrant function(s) are often assocd. with human disease. Thus, to advance therapeutics and to probe signal transduction cascades, there is considerable interest in the development of inhibitors that can selectively target protein kinases. However, identifying specific compds. against such a large array of protein kinases is difficult to routinely achieve using traditional activity assays, where purified protein kinases are necessary. Toward a simple, rapid, and practical method for identifying specific inhibitors, the authors describe the development and application of a split-protein methodol. using a coiled-coil-assisted three-hybrid system. In this approach, a protein kinase of interest is attached to the C-terminal fragment of split-firefly luciferase and the coiled-coil Fos, which is specific for the coiled-coil Jun, is attached to the N-terminal fragment. Upon addn. of Jun conjugated to a pan-kinase inhibitor such as staurosporine, a three-hybrid complex was established with concomitant reassembly of the split-luciferase enzyme. An inhibitor can be potentially identified by the commensurate loss in split-luciferase activity by displacement of the modified staurosporine. This new three-hybrid approach is potentially general by testing protein kinases from the different kinase families. To interrogate whether this method allows for screening inhibitors, the authors tested six different protein kinases against a library of 80 known protein kinase inhibitors. Finally, this three-hybrid system can potentially provide a rapid method for structure/function anal. as well as aid in the identification of allosteric inhibitors.

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19. 19

    Reininger, L.; Wilkes, J. M.; Bourgade, H.; Miranda-Saavedra, D.; Doerig, C. An Essential Aurora-Related Kinase Transiently Associates with Spindle Pole Bodies during Plasmodium Falciparum Erythrocytic Schizogony. Mol. Microbiol. 2011, 79, 205– 221,  DOI: 10.1111/j.1365-2958.2010.07442.x

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    19

    An essential Aurora-related kinase transiently associates with spindle pole bodies during Plasmodium falciparum erythrocytic schizogony

    Reininger, Luc; Wilkes, Jonathan M.; Bourgade, Helene; Miranda-Saavedra, Diego; Doerig, Christian

    Molecular Microbiology (2011), 79 (1), 205-221CODEN: MOMIEE; ISSN:0950-382X. (Wiley-Blackwell)

    Aurora kinases compose a family of conserved Ser/Thr protein kinases playing essential roles in eukaryotic cell division. To date, Aurora homologues remain uncharacterized in the protozoan phylum Apicompexa. In malaria parasites, the characterization of Aurora kinases may help understand the cell cycle control during erythrocytic schizogony where asynchronous nuclear divisions occur. In this study, we revisited the kinome of Plasmodium falciparum and identified three Aurora-related kinases, Pfark-1, -2, -3. Among these, Pfark-1 is highly conserved in malaria parasites and also appears to be conserved across Apicomplexa. By tagging the endogenous Pfark-1 gene with the green fluorescent protein (GFP) in live parasites, we show that the Pfark-1-GFP protein forms paired dots assocd. with only a subset of nuclei within individual schizonts. Immunofluorescence anal. using an anti-α-tubulin antibody strongly suggests a recruitment of Pfark-1 at duplicated spindle pole bodies at the entry of the M phase of the cell cycle. Unsuccessful attempts at disrupting the Pfark-1 gene with a knockout construct further indicate that Pfark-1 is required for parasite growth in red blood cells. This study provides new insights into the cell cycle control of malaria parasites and reports the importance of Aurora kinases as potential targets for new antimalarials.

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20. 20

    Berry, L.; Chen, C.-T.; Reininger, L.; Carvalho, T. G.; El Hajj, H.; Morlon-Guyot, J.; Bordat, Y.; Lebrun, M.; Gubbels, M.-J.; Doerig, C.; Daher, W. The Conserved Apicomplexan Aurora Kinase TgArk3 Is Involved in Endodyogeny, Duplication Rate and Parasite Virulence. Cell. Microbiol. 2016, 18, 1106– 1120,  DOI: 10.1111/cmi.12571

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    20

    The conserved apicomplexan Aurora kinase TgArk3 is involved in endodyogeny, duplication rate and parasite virulence

    Berry, Laurence; Chen, Chun-Ti; Reininger, Luc; Carvalho, Teresa G.; El Hajj, Hiba; Morlon-Guyot, Juliette; Bordat, Yann; Lebrun, Maryse; Gubbels, Marc-Jan; Doerig, Christian; Daher, Wassim

    Cellular Microbiology (2016), 18 (8), 1106-1120CODEN: CEMIF5; ISSN:1462-5814. (Wiley-Blackwell)

    Aurora kinases are eukaryotic serine/threonine protein kinases that regulate key events assocd. with chromatin condensation, centrosome and spindle function and cytokinesis. Elucidating the roles of Aurora kinases in apicomplexan parasites is crucial to understand the cell cycle control during Plasmodium schizogony or Toxoplasma endodyogeny. Here, the authors report on the localization of two previously uncharacterized Toxoplasma Aurora-related kinases (Ark2 and Ark3) in tachyzoites and of the uncharacterized Ark3 ortholog in Plasmodium falciparum erythrocytic stages. In Toxoplasma gondii, TgArk2 and TgArk3 conc. at specific subcellular structures linked to parasite division: the mitotic spindle and intranuclear mitotic structures (TgArk2), and the outer core of the centrosome and the budding daughter cells cytoskeleton (TgArk3). By tagging the endogenous PfArk3 gene with the green fluorescent protein in live parasites, PfArk3 protein expression was shown to peak late in schizogony and localize at the periphery of budding schizonts. Disruption of the TgArk2 gene reveals no essential function for tachyzoite propagation in vitro, which is surprising giving that the P. falciparum and P. berghei orthologs are essential for erythrocyte schizogony. In contrast, knock-down of TgArk3 protein results in pronounced defects in parasite division and a major growth deficiency. TgArk3-depleted parasites display several defects, such as reduced parasite growth rate, delayed egress and parasite duplication, defect in rosette formation, reduced parasite size and invasion efficiency and lack of virulence in mice. The authors' study provides new insights into cell cycle control in Toxoplasma and malaria parasites and highlights Aurora kinase 3 as potential drug target.

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21. 21

    Patel, G.; Roncal, N. E.; Lee, P. J.; Leed, S. E.; Erath, J.; Rodriguez, A.; Sciotti, R. J.; Pollastri, M. P. Repurposing Human Aurora Kinase Inhibitors as Leads for Anti-Protozoan Drug Discovery. Med. Chem. Commun. 2014, 5, 655– 658,  DOI: 10.1039/C4MD00045E

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22. 22

    Morahan, B. J.; Abrie, C.; Al-Hasani, K.; Batty, M. B.; Corey, V.; Cowell, A. N.; Niemand, J.; Winzeler, E. A.; Birkholtz, L.-M.; Doerig, C.; Garcia-Bustos, J. F. Human Aurora Kinase Inhibitor Hesperadin Reveals Epistatic Interaction between Plasmodium Falciparum PfArk1 and PfNek1 Kinases. Commun. Biol. 2020, 3, 701,  DOI: 10.1038/s42003-020-01424-z

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    22

    Human Aurora kinase inhibitor Hesperadin reveals epistatic interaction between Plasmodium falciparum PfArk1 and PfNek1 kinases

    Morahan, Belinda J.; Abrie, Clarissa; Al-Hasani, Keith; Batty, Mitchell B.; Corey, Victoria; Cowell, Anne N.; Niemand, Jandeli; Winzeler, Elizabeth A.; Birkholtz, Lyn-Marie; Doerig, Christian; Garcia-Bustos, Jose F.

    Communications Biology (2020), 3 (1), 701CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)

    Abstr.: Mitosis has been validated by numerous anti-cancer drugs as being a druggable process, and selective inhibition of parasite proliferation provides an obvious opportunity for therapeutic intervention against malaria. Mitosis is controlled through the interplay between several protein kinases and phosphatases. We show here that inhibitors of human mitotic kinases belonging to the Aurora family inhibit P. falciparum proliferation in vitro with various potencies, and that a genetic selection for mutant parasites resistant to one of the drugs, Hesperadin, identifies a resistance mechanism mediated by a member of a different kinase family, PfNek1 (PF3D7_1228300). Intriguingly, loss of PfNek1 catalytic activity provides protection against drug action. This points to an undescribed functional interaction between Ark and Nek kinases and shows that existing inhibitors can be used to validate addnl. essential and druggable kinase functions in the parasite.

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23. 23

    Lye, Y. M.; Chan, M.; Sim, T.-S. Pfnek3: An Atypical Activator of a MAP Kinase in Plasmodium Falciparum. FEBS Lett. 2006, 580, 6083– 6092,  DOI: 10.1016/j.febslet.2006.10.003

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    23

    Pfnek3: An atypical activator of a MAP kinase in Plasmodium falciparum

    Lye, Yu Min; Chan, Maurice; Sim, Tiow-Suan

    FEBS Letters (2006), 580 (26), 6083-6092CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)

    The canonical mitogen-activated protein kinase (MAPK) signal cascade was previously suggested to be atypical in the malaria parasite. This raises queries on the existence of alternative mediators of plasmodial MAPK pathways. This study describes, Pfnek3, a malarial protein kinase belonging to the NIMA (Never in Mitosis, Aspergillus) family. Endogenous Pfnek3 is expressed during late asexual to gametocyte stages and lacks some classical protein kinase sequence motifs. Moreover, Pfnek3 is phylogenetically distant from mammalian NIMA-kinases. Recombinant Pfnek3 was able to phosphorylate and stimulate a malarial MAPK (Pfmap2). Contrastingly, this was not obsd. with two other kinases, Pfmap1 and human MAPK1, suggesting that the Pfnek3-Pfmap2 interaction may be specific for Pfmap2 regulation. In summary, our data reveal a malarial NIMA-kinase with the potential to regulate a MAPK. Possessing biochem. properties divergent from classical mammalian NIMA-kinases, Pfnek3 could potentially be an attractive target for parasite-selective anti-malarials.

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24. 24

    Low, H.; Lye, Y. M.; Sim, T.-S. Pfnek3 Functions as an Atypical MAPKK in Plasmodium Falciparum. Biochem. Biophys. Res. Commun. 2007, 361, 439– 444,  DOI: 10.1016/j.bbrc.2007.07.047

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    24

    Pfnek3 functions as an atypical MAPKK in Plasmodium falciparum

    Low, Huiyu; Lye, Yu Min; Sim, Tiow-Suan

    Biochemical and Biophysical Research Communications (2007), 361 (2), 439-444CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)

    Eukaryotes generally rely on signal transduction by mitogen-activated protein kinases (MAPKs) for activating their regulatory pathways. However, the presence of a complete MAPK cascade in Plasmodium falciparum is debatable because a search of the entire genome did not portray known MAPK kinase (MAPKK) sequences. Via homol. PCR expts., only two copies of plasmodial MAPK homologs (Pfmap1 and Pfmap2) have been identified but their upstream activators remain unknown. In an earlier expt., Pfnek3 was found to be an unusual activator of Pfmap2 in vitro expts., despite its mol. identity as a malarial protein kinase from the NIMA (Never in Mitosis, Aspergillus) family. In this study, the role of Pfnek3 as a likely upstream MAPKK is defined through mol. and biochem. characterization. Since a previous report proposes a TSH motif as an activation site of Pfmap2, its site-directed mutants, T290A, S291A, and H292K were constructed to elucidate the involvement of Pfnek3 in phosphorylating and activating Pfmap2 in a battery of kinase assays. The results suggested that residue T290 is the site of phosphorylation by Pfnek3. This supposition was further supported by liq. chromatog. mass spectrometry. Although P. falciparum does not appear to possess a conventional MAPK cascade, they may rely on other kinases such as Pfnek3 to carry out similar phosphorylation to activate its signaling pathways.

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25. 25

    Ong, H. W.; Truong, A.; Kwarcinski, F.; de Silva, C.; Avalani, K.; Havener, T. M.; Chirgwin, M.; Galal, K. A.; Willis, C.; Krämer, A.; Liu, S.; Knapp, S.; Derbyshire, E. R.; Zutshi, R.; Drewry, D. H. Discovery of Potent Plasmodium Falciparum Protein Kinase 6 (PfPK6) Inhibitors with a Type II Inhibitor Pharmacophore. Eur. J. Med. Chem. 2023, 249, 115043,  DOI: 10.1016/j.ejmech.2022.115043

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    25

    Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore

    Ong, Han Wee; Truong, Anna; Kwarcinski, Frank; de Silva, Chandi; Avalani, Krisha; Havener, Tammy M.; Chirgwin, Michael; Galal, Kareem A.; Willis, Caleb; Kramer, Andreas; Liu, Shubin; Knapp, Stefan; Derbyshire, Emily R.; Zutshi, Reena; Drewry, David H.

    European Journal of Medicinal Chemistry (2023), 249 (), 115043CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of action. We report the discovery of Ki8751 as an inhibitor of essential kinase PfPK6. 79 derivs. were designed, synthesized and evaluated for PfPK6 inhibition and antiplasmodial activity. Using group efficiency analyses, we established the importance of key groups on the scaffold consistent with a type II inhibitor pharmacophore. We highlight modifications on the tail group that contribute to antiplasmodial activity, cumulating in the discovery of compd. 67, a PfPK6 inhibitor (IC50 = 13 nM) active against the P. falciparum blood stage (EC50 = 160 nM), and compd. 79, a PfPK6 inhibitor (IC50 < 5 nM) with dual-stage antiplasmodial activity against P. falciparum blood stage (EC50 = 39 nM) and against P. berghei liver stage (EC50 = 220 nM).

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26. 26

    Philip, N.; Haystead, T. A. Characterization of a UBC13 Kinase in Plasmodium Falciparum. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 7845– 7850,  DOI: 10.1073/pnas.0611601104

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    26

    Characterization of a UBC13 kinase in Plasmodium falciparum

    Philip, Nisha; Haystead, Timothy A.

    Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (19), 7845-7850CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Protein kinases are generally recognized as attractive drug targets to treat a variety of human diseases. Recent anal. of the Plasmodium falciparum kinome identified several kinases that are entirely unique to Plasmodium species. The specific functions and targets of most of these enzymes remain largely unknown. Here, we have identified a P. falciparum kinase (PfPK9/PF13_0085 ORF) that does not cluster with any of the typical eukaryotic protein kinases. PfPK9 protein expression was induced ≈18 h after red blood cell infection, and was mainly localized to the parasitophorous vacuolar membrane as well as the cytosol. Recombinant PfPK9 autophosphorylated in vitro and specifically phosphorylated the exogenous substrate histone H1, indicating that it is catalytically active. Phosphopeptide mapping studies showed that autophosphorylation occurred at three residues: T082, T265, and T269. We identified a P. falciparum homolog of the E2 ubiquitin-conjugating enzyme 13 (UBC13) as an endogenous substrate for PfPK9. PfPK9 phosphorylated UBC13 at S106, a highly conserved residue among eukaryotic E2s, and suppressed its ubiquitin-conjugating activity. Our findings not only describe a previously uncharacterized Plasmodium kinase and its likely in vivo target, but also suggest that modulation of UBC13 activity by phosphorylation may be a common regulatory mechanism in eukaryotes.

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27. 27

    Raphemot, R.; Eubanks, A. L.; Toro-Moreno, M.; Geiger, R. A.; Hughes, P. F.; Lu, K.-Y.; Haystead, T. A. J.; Derbyshire, E. R. Plasmodium PK9 Inhibitors Promote Growth of Liver-Stage Parasites. Cell Chem. Biol. 2019, 26, 411– 419,  DOI: 10.1016/j.chembiol.2018.11.003

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    27

    Plasmodium PK9 Inhibitors Promote Growth of Liver-Stage Parasites

    Raphemot, Rene; Eubanks, Amber Leigh; Toro-Moreno, Maria; Geiger, Rechel Anne; Hughes, Philip Floyd; Lu, Kuan-Yi; Haystead, Timothy Arthur James; Derbyshire, Emily Rose

    Cell Chemical Biology (2019), 26 (3), 411-419.e7CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)

    There is a scarcity of pharmacol. tools to interrogate protein kinase function in Plasmodium parasites, the causative agent of malaria. Among Plasmodiums protein kinases, those characterized as atypical represent attractive drug targets as they lack sequence similarity to human proteins. Here, we describe takinib as a small mol. to bind the atypical P. falciparum protein kinase 9 (PfPK9). PfPK9 phosphorylates the Plasmodium E2 ubiquitin-conjugating enzyme PfUBC13, which mediates K63-linkage-specific polyubiquitination. Takinib is a potent human TAK1 inhibitor, thus we developed the Plasmodium-selective takinib analog HS220. We demonstrate that takinib and HS220 decrease K63-linked ubiquitination in P. falciparum, suggesting PfPK9 inhibition in cells. Takinib and HS220 induce a unique phenotype where parasite size in hepatocytes increases, yet high compd. concns. decrease the no. of parasites. Our studies highlight the role of PK9 in regulating parasite development and the potential of targeting Plasmodium kinases for malaria control.

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28. 28

    Maneekesorn, S.; Knuepfer, E.; Green, J. L.; Prommana, P.; Uthaipibull, C.; Srichairatanakool, S.; Holder, A. A. Deletion of Plasmodium Falciparum Ubc13 Increases Parasite Sensitivity to the Mutagen, Methyl Methanesulfonate and Dihydroartemisinin. Sci. Rep. 2021, 11, 21791,  DOI: 10.1038/s41598-021-01267-6

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    28

    Deletion of Plasmodium falciparum ubc13 increases parasite sensitivity to the mutagen, methyl methanesulfonate and dihydroartemisinin

    Maneekesorn, Supawadee; Knuepfer, Ellen; Green, Judith L.; Prommana, Parichat; Uthaipibull, Chairat; Srichairatanakool, Somdet; Holder, Anthony A.

    Scientific Reports (2021), 11 (1), 21791CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)

    The inducible Di-Cre system was used to delete the putative ubiquitin-conjugating enzyme 13 gene (ubc13) of Plasmodium falciparum to study its role in ubiquitylation and the functional consequence during the parasite asexual blood stage. Deletion resulted in a significant redn. of parasite growth in vitro, reduced ubiquitylation of the Lys63 residue of ubiquitin attached to protein substrates, and an increased sensitivity of the parasite to both the mutagen, Me methanesulfonate and the antimalarial drug dihydroartemisinin (DHA), but not chloroquine. The parasite was also sensitive to the UBC13 inhibitor NSC697923. The data suggest that this gene does code for an ubiquitin conjugating enzyme responsible for K63 ubiquitylation, which is important in DNA repair pathways as was previously demonstrated in other organisms. The increased parasite sensitivity to DHA in the absence of ubc13 function indicates that DHA may act primarily through this pathway and that inhibitors of UBC13 may both enhance the efficacy of this antimalarial drug and directly inhibit parasite growth.

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29. 29

    Kumar, A.; Vaid, A.; Syin, C.; Sharma, P. PfPKB, a Novel Protein Kinase B-like Enzyme from Plasmodium Falciparum I. Identification, Characterization, and Possible Role in Parasite Development. J. Biol. Chem. 2004, 279, 24255– 24264,  DOI: 10.1074/jbc.M312855200

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    29

    PfPKB, a Novel Protein Kinase B-like Enzyme from Plasmodium falciparum: I. Identification, characterization, and possible role in parasite development

    Kumar, Amit; Vaid, Ankush; Syin, Chiang; Sharma, Pushkar

    Journal of Biological Chemistry (2004), 279 (23), 24255-24264CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Extracellular signals control various important functions of a eukaryotic cell, which is often achieved by regulating a battery of protein kinases and phosphatases. Protein Kinase B (PKB) is an important member of the phosphatidylinositol 3-kinase-dependent signaling pathways in several eukaryotes, but the role of PKB in protozoan parasites is not known. We have identified a protein kinase B homolog in Plasmodium falciparum (PfPKB) that is expressed mainly in the schizonts and merozoites. Even though PfPKB shares high sequence homol. with PKB catalytic domain, it lacks a pleckstrin homol. domain typically found at the N terminus of the mammalian enzyme. Biochem. studies performed to understand the mechanism of PfPKB catalytic activation suggested that (i) its activation is dependent on autophosphorylation of a serine residue (Ser-271) in its activation loop region and (ii) PfPKB has an unusual N-terminal region that was found to neg. regulate its catalytic activity. We also identified an inhibitor of PfPKB activity that also inhibits P. falciparum growth, suggesting that this enzyme may be important for the development of the parasite.

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30. 30

    Baum, J.; Richard, D.; Healer, J.; Rug, M.; Krnajski, Z.; Gilberger, T.-W.; Green, J. L.; Holder, A. A.; Cowman, A. F. A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites. J. Biol. Chem. 2006, 281, 5197– 5208,  DOI: 10.1074/jbc.M509807200

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    30

    A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites

    Baum, Jake; Richard, Dave; Healer, Julie; Rug, Melanie; Krnajski, Zita; Gilberger, Tim-Wolf; Green, Judith L.; Holder, Anthony A.; Cowman, Alan F.

    Journal of Biological Chemistry (2006), 281 (8), 5197-5208CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Apicomplexan parasites constitute one of the most significant groups of pathogens infecting humans and animals. The liver stage sporozoites of Plasmodium spp. and tachyzoites of Toxoplasma gondii, the causative agents of malaria and toxoplasmosis, resp., use a unique mode of locomotion termed gliding motility to invade host cells and cross cell substrates. This amoeboid-like movement uses a parasite adhesin from the thrombospondin-related anonymous protein (TRAP) family and a set of proteins linking the extracellular adhesin, via an actin-myosin motor, to the inner membrane complex. The Plasmodium blood stage merozoite, however, does not exhibit gliding motility. Here we show that homologs of the key proteins that make up the motor complex, including the recently identified glideosome-assocd. proteins 45 and 50 (GAP45 and GAP50), are present in P. falciparum merozoites and appear to function in erythrocyte invasion. Furthermore, we identify a merozoite TRAP homolog, termed MTRAP, a micronemal protein that shares key features with TRAP, including a thrombospondin repeat domain, a putative rhomboid-protease cleavage site, and a cytoplasmic tail that, in vitro, binds the actin-binding protein aldolase. Anal. of other parasite genomes shows that the components of this motor complex are conserved across diverse Apicomplexan genera. Conservation of the motor complex suggests that a common mol. mechanism underlies all Apicomplexan motility, which, given its unique properties, highlights a no. of novel targets for drug intervention to treat major diseases of humans and livestock.

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    Jones, M. L.; Kitson, E. L.; Rayner, J. C. Plasmodium Falciparum Erythrocyte Invasion: A Conserved Myosin Associated Complex. Mol. Biochem. Parasitol. 2006, 147, 74– 84,  DOI: 10.1016/j.molbiopara.2006.01.009

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    Plasmodium falciparum erythrocyte invasion: A conserved myosin associated complex

    Jones, Matthew L.; Kitson, Erika L.; Rayner, Julian C.

    Molecular & Biochemical Parasitology (2006), 147 (1), 74-84CODEN: MBIPDP; ISSN:0166-6851. (Elsevier Ltd.)

    Host cell invasion by apicomplexan parasites is powered by an actin/myosin motor complex that has been most thoroughly described in Toxoplasma gondii tachyzoites. In T. gondii, two inner membrane complex (IMC) proteins, the peripheral protein TgGAP45 and the transmembrane protein TgGAP50, form a complex with the myosin, TgMyoA, and its light chain, TgMLC1. This complex, referred to as the glideosome, anchors the invasion motor to the IMC. We have identified and characterized orthologues of TgMLC1, TgGAP45 and TgGAP50 in blood-stages of the major human pathogen Plasmodium falciparum, supporting the idea that the same basic complex drives host cell invasion across the apicomplexan phylum. The P. falciparum glideosome proteins are transcribed, expressed and localized in a manner consistent with a role in erythrocyte invasion. Furthermore, PfMyoA interacts with PfMTIP through broadly conserved mechanisms described in other eukaryotes, and forms a complex with PfGAP45 and PfGAP50 in late schizonts and merozoites. P. falciparum is known to use multiple alternative invasion pathways to enter erythrocytes, hampering vaccine development efforts targeting erythrocyte invasion. Our data suggests that the same invasion motor underpins all alternative invasion pathways, making it an attractive target for the development of novel intervention strategies.

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32. 32

    Thomas, D. C.; Ahmed, A.; Gilberger, T. W.; Sharma, P. Regulation of Plasmodium Falciparum Glideosome Associated Protein 45 (PfGAP45) Phosphorylation. PLoS One 2012, 7, e35855  DOI: 10.1371/journal.pone.0035855

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    32

    Regulation of Plasmodium falciparum Glideosome Associated Protein 45 (PfGAP45) phosphorylation

    Thomas, Divya Catherine; Ahmed, Anwar; Gilberger, Tim Wolf; Sharma, Pushkar

    PLoS One (2012), 7 (4), e35855CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

    The actomyosin motor complex of the glideosome provides the force needed by apicomplexan parasites such as Toxoplasma gondii (Tg) and Plasmodium falciparum (Pf) to invade their host cells and for gliding motility of their motile forms. Glideosome Assocd. Protein 45 (PfGAP45) is an essential component of the glideosome complex as it facilitates anchoring and effective functioning of the motor. Dissection of events that regulate PfGAP45 may provide insights into how the motor and the glideosome operate. We found that PfGAP45 is phosphorylated in response to Phospholipase C (PLC) and calcium signaling. It is phosphorylated by P. falciparum kinases Protein Kinase B (PfPKB) and Calcium Dependent Protein Kinase 1 (PfCDPK1), which are calcium dependent enzymes, at S89, S103 and S149. The Phospholipase C pathway influenced the phosphorylation of S103 and S149. The phosphorylation of PfGAP45 at these sites is differentially regulated during parasite development. The localization of PfGAP45 and its assocn. may be independent of the phosphorylation of these sites. PfGAP45 regulation in response to calcium fits in well with the previously described role of calcium in host cell invasion by malaria parasite.

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33. 33

    Vaid, A.; Thomas, D. C.; Sharma, P. Role of Ca2+/Calmodulin-PfPKB Signaling Pathway in Erythrocyte Invasion by Plasmodium Falciparum. J. Biol. Chem. 2008, 283, 5589– 5597,  DOI: 10.1074/jbc.M708465200

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    33

    Role of Ca2+/calmodulin-PfPKB signaling pathway in erythrocyte invasion by Plasmodium falciparum

    Vaid, Ankush; Thomas, Divya C.; Sharma, Pushkar

    Journal of Biological Chemistry (2008), 283 (9), 5589-5597CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Mol. mechanisms by which signaling pathways operate in the malaria parasite and control its development are promiscuous. Recently, we reported the identification of a signaling pathway in Plasmodium falciparum, which involves activation of protein kinase B-like enzyme (PfPKB) by calcium/calmodulin. Studies carried out to elucidate the function of this pathway suggested that it may be important for erythrocyte invasion. Blocking the function of the upstream activators of this pathway, calmodulin and phospholipase C, resulted in impaired invasion. To evaluate if this signaling cascade controls invasion by regulating PfPKB, inhibitors against this kinase were developed. PfPKB inhibitors dramatically reduced the ability of the parasite to invade erythrocytes. Furthermore, we demonstrate that PfPKB assocs. with actin-myosin motor and phosphorylates PfGAP45 (glideosome-assocd. protein 45), one of the important components of the motor complex, which may help explain its role in erythrocyte invasion.

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34. 34

    Jumper, J.; Evans, R.; Pritzel, A.; Green, T.; Figurnov, M.; Ronneberger, O.; Tunyasuvunakool, K.; Bates, R.; Žídek, A.; Potapenko, A.; Bridgland, A.; Meyer, C.; Kohl, S. A. A.; Ballard, A. J.; Cowie, A.; Romera-Paredes, B.; Nikolov, S.; Jain, R.; Adler, J.; Back, T.; Petersen, S.; Reiman, D.; Clancy, E.; Zielinski, M.; Steinegger, M.; Pacholska, M.; Berghammer, T.; Bodenstein, S.; Silver, D.; Vinyals, O.; Senior, A. W.; Kavukcuoglu, K.; Kohli, P.; Hassabis, D. Highly Accurate Protein Structure Prediction with AlphaFold. Nature 2021, 596, 583– 589,  DOI: 10.1038/s41586-021-03819-2

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    34

    Highly accurate protein structure prediction with AlphaFold

    Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ; Zidek, Augustin; Potapenko, Anna; Bridgland, Alex; Meyer, Clemens; Kohl, Simon A. A.; Ballard, Andrew J.; Cowie, Andrew; Romera-Paredes, Bernardino; Nikolov, Stanislav; Jain, Rishub; Adler, Jonas; Back, Trevor; Petersen, Stig; Reiman, David; Clancy, Ellen; Zielinski, Michal; Steinegger, Martin; Pacholska, Michalina; Berghammer, Tamas; Bodenstein, Sebastian; Silver, David; Vinyals, Oriol; Senior, Andrew W.; Kavukcuoglu, Koray; Kohli, Pushmeet; Hassabis, Demis

    Nature (London, United Kingdom) (2021), 596 (7873), 583-589CODEN: NATUAS; ISSN:0028-0836. (Nature Portfolio)

    Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous exptl. effort, the structures of around 100,000 unique proteins have been detd., but this represents a small fraction of the billions of known protein sequences. Structural coverage is bottlenecked by the months to years of painstaking effort required to det. a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence-the structure prediction component of the 'protein folding problem'-has been an important open research problem for more than 50 years. Despite recent progress, existing methods fall far short of at. accuracy, esp. when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with at. accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Crit. Assessment of protein Structure Prediction (CASP14), demonstrating accuracy competitive with exptl. structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates phys. and biol. knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.

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35. 35

    Varadi, M.; Anyango, S.; Deshpande, M.; Nair, S.; Natassia, C.; Yordanova, G.; Yuan, D.; Stroe, O.; Wood, G.; Laydon, A.; Žídek, A.; Green, T.; Tunyasuvunakool, K.; Petersen, S.; Jumper, J.; Clancy, E.; Green, R.; Vora, A.; Lutfi, M.; Figurnov, M.; Cowie, A.; Hobbs, N.; Kohli, P.; Kleywegt, G.; Birney, E.; Hassabis, D.; Velankar, S. AlphaFold Protein Structure Database: Massively Expanding the Structural Coverage of Protein-Sequence Space with High-Accuracy Models. Nucleic Acids Res. 2022, 50, D439– D444,  DOI: 10.1093/nar/gkab1061

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    35

    AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models

    Varadi, Mihaly; Anyango, Stephen; Deshpande, Mandar; Nair, Sreenath; Natassia, Cindy; Yordanova, Galabina; Yuan, David; Stroe, Oana; Wood, Gemma; Laydon, Agata; Zidek, Augustin; Green, Tim; Tunyasuvunakool, Kathryn; Petersen, Stig; Jumper, John; Clancy, Ellen; Green, Richard; Vora, Ankur; Lutfi, Mira; Figurnov, Michael; Cowie, Andrew; Hobbs, Nicole; Kohli, Pushmeet; Kleywegt, Gerard; Birney, Ewan; Hassabis, Demis; Velankar, Sameer

    Nucleic Acids Research (2022), 50 (D1), D439-D444CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)

    The AlphaFold Protein Structure Database is an openly accessible, extensive database of high-accuracy protein-structure predictions. Powered by AlphaFold v2.0 of DeepMind, it has enabled an unprecedented expansion of the structural coverage of the known protein-sequence space. AlphaFold DB provides programmatic access to and interactive visualization of predicted at. coordinates, per-residue and pairwise model-confidence ests. and predicted aligned errors. The initial release of AlphaFold DB contains over 360,000 predicted structures across 21 model-organism proteomes, which will soon be expanded to cover most of the (over 100 million) representative sequences from the UniRef90 data set.

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36. 36

    van Linden, O. P. J.; Kooistra, A. J.; Leurs, R.; de Esch, I. J. P.; de Graaf, C. KLIFS: A Knowledge-Based Structural Database To Navigate Kinase–Ligand Interaction Space. J. Med. Chem. 2014, 57, 249– 277,  DOI: 10.1021/jm400378w

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    KLIFS: A Knowledge-Based Structural Database To Navigate Kinase-Ligand Interaction Space

    van Linden, Oscar P. J.; Kooistra, Albert J.; Leurs, Rob; de Esch, Iwan J. P.; de Graaf, Chris

    Journal of Medicinal Chemistry (2014), 57 (2), 249-277CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    A review. Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic anal. of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chem. scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.

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37. 37

    Lategahn, J.; Tumbrink, H. L.; Schultz-Fademrecht, C.; Heimsoeth, A.; Werr, L.; Niggenaber, J.; Keul, M.; Parmaksiz, F.; Baumann, M.; Menninger, S.; Zent, E.; Landel, I.; Weisner, J.; Jeyakumar, K.; Heyden, L.; Russ, N.; Müller, F.; Lorenz, C.; Brägelmann, J.; Spille, I.; Grabe, T.; Müller, M. P.; Heuckmann, J. M.; Klebl, B. M.; Nussbaumer, P.; Sos, M. L.; Rauh, D. Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors. J. Med. Chem. 2022, 65, 6643– 6655,  DOI: 10.1021/acs.jmedchem.1c02080

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    37

    Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors

    Lategahn, Jonas; Tumbrink, Hannah L.; Schultz-Fademrecht, Carsten; Heimsoeth, Alena; Werr, Lisa; Niggenaber, Janina; Keul, Marina; Parmaksiz, Fatma; Baumann, Matthias; Menninger, Sascha; Zent, Eldar; Landel, Ina; Weisner, Joern; Jeyakumar, Kirujan; Heyden, Leonie; Russ, Nicole; Mueller, Fabienne; Lorenz, Carina; Braegelmann, Johannes; Spille, Inga; Grabe, Tobias; Mueller, Matthias P.; Heuckmann, Johannes M.; Klebl, Bert M.; Nussbaumer, Peter; Sos, Martin L.; Rauh, Daniel

    Journal of Medicinal Chemistry (2022), 65 (9), 6643-6655CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Despite the clin. efficacy of epidermal growth factor receptor (EGFR) inhibitors, a subset of patients with non-small cell lung cancer displays insertion mutations in exon20 in EGFR and Her2 with limited treatment options. Here, we present the development and characterization of the novel covalent inhibitors LDC8201 and LDC0496 based on a 1H-pyrrolo[2,3-b]pyridine scaffold. They exhibited intense inhibitory potency toward EGFR and Her2 exon20 insertion mutations as well as selectivity over wild type EGFR and within the kinome. Complex crystal structures with the inhibitors and biochem. and cellular on-target activity document their favorable binding characteristics. Ultimately, we obsd. tumor shrinkage in mice engrafted with patient-derived EGFR-H773_V774insNPH mutant cells during treatment with LDC8201. Together, these results highlight the potential of covalent pyrrolopyridines as inhibitors to target exon20 insertion mutations.

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38. 38

    Alam, M.; Beevers, R. E.; Ceska, T.; Davenport, R. J.; Dickson, K. M.; Fortunato, M.; Gowers, L.; Haughan, A. F.; James, L. A.; Jones, M. W.; Kinsella, N.; Lowe, C.; Meissner, J. W. G.; Nicolas, A. L.; Perry, B. G.; Phillips, D. J.; Pitt, W. R.; Platt, A.; Ratcliffe, A. J.; Sharpe, A.; Tait, L. J. Synthesis and SAR of Aminopyrimidines as Novel C-Jun N-Terminal Kinase (JNK) Inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 3463– 3467,  DOI: 10.1016/j.bmcl.2007.03.078

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    Synthesis and SAR of aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors

    Alam, Mahbub; Beevers, Rebekah E.; Ceska, Tom; Davenport, Richard J.; Dickson, Karen M.; Fortunato, Mara; Gowers, Lewis; Haughan, Alan F.; James, Lynwen A.; Jones, Mark W.; Kinsella, Natasha; Lowe, Christopher; Meissner, Johannes W. G.; Nicolas, Anne-Lise; Perry, Benjamin G.; Phillips, David J.; Pitt, William R.; Platt, Adam; Ratcliffe, Andrew J.; Sharpe, Andrew; Tait, Laura J.

    Bioorganic & Medicinal Chemistry Letters (2007), 17 (12), 3463-3467CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)

    The development of a series of aminopyrimidines, e.g., I, as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay were discussed.

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39. 39

    Lange, A.; Günther, M.; Büttner, F. M.; Zimmermann, M. O.; Heidrich, J.; Hennig, S.; Zahn, S.; Schall, C.; Sievers-Engler, A.; Ansideri, F.; Koch, P.; Laemmerhofer, M.; Stehle, T.; Laufer, S. A.; Boeckler, F. M. Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond. J. Am. Chem. Soc. 2015, 137, 14640– 14652,  DOI: 10.1021/jacs.5b07090

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    Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond

    Lange, Andreas; Guenther, Marcel; Buettner, Felix Michael; Zimmermann, Markus O.; Heidrich, Johannes; Hennig, Susanne; Zahn, Stefan; Schall, Christoph; Sievers-Engler, Adrian; Ansideri, Francesco; Koch, Pierre; Laemmerhofer, Michael; Stehle, Thilo; Laufer, Stefan A.; Boeckler, Frank M.

    Journal of the American Chemical Society (2015), 137 (46), 14640-14652CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    We target the gatekeeper MET146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X···S halogen bonds in mol. design using computational, synthetic, structural and biophys. techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calcd. interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their σ-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Detg. the crystal structure of the iodine deriv. in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cε of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%).

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40. 40

    Hole, A. J.; Baumli, S.; Shao, H.; Shi, S.; Huang, S.; Pepper, C.; Fischer, P. M.; Wang, S.; Endicott, J. A.; Noble, M. E. Comparative Structural and Functional Studies of 4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile CDK9 Inhibitors Suggest the Basis for Isotype Selectivity. J. Med. Chem. 2013, 56, 660– 670,  DOI: 10.1021/jm301495v

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    40

    Comparative Structural and Functional Studies of 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 Inhibitors Suggest the Basis for Isotype Selectivity

    Hole, Alison J.; Baumli, Sonja; Shao, Hao; Shi, Shenhua; Huang, Shiliang; Pepper, Chris; Fischer, Peter M.; Wang, Shudong; Endicott, Jane A.; Noble, Martin E.

    Journal of Medicinal Chemistry (2013), 56 (3), 660-670CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes pos. transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temp. of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorometry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compds. is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-D-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts.

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41. 41

    Galkin, A. V.; Melnick, J. S.; Kim, S.; Hood, T. L.; Li, N.; Li, L.; Xia, G.; Steensma, R.; Chopiuk, G.; Jiang, J.; Wan, Y.; Ding, P.; Liu, Y.; Sun, F.; Schultz, P. G.; Gray, N. S.; Warmuth, M. Identification of NVP-TAE684, a Potent, Selective, and Efficacious Inhibitor of NPM-ALK. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 270– 275,  DOI: 10.1073/pnas.0609412103

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    Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK

    Galkin, Anna V.; Melnick, Jonathon S.; Kim, Sunjoon; Hood, Tami L.; Li, Nanxin; Li, Lintong; Xia, Gang; Steensma, Ruo; Chopiuk, Greg; Wan, Yongqin; Ding, Peter; Liu, Yi; Sun, Fangxian; Schultz, Peter G.; Gray, Nathanael S.; Warmuth, Markus

    Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (1), 270-275CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large cell lymphomas (ALCLs). We have identified a highly potent and selective small-mol. ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC50 values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-pos. ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.

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    Kothe, M.; Kohls, D.; Low, S.; Coli, R.; Rennie, G. R.; Feru, F.; Kuhn, C.; Ding, Y.-H. Selectivity-Determining Residues in Plk1. Chem. Biol. Drug Des. 2007, 70, 540– 546,  DOI: 10.1111/j.1747-0285.2007.00594.x

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    Selectivity-determining residues in Plk1

    Kothe, Michael; Kohls, Darcy; Low, Simon; Coli, Rocco; Rennie, Glen R.; Feru, Frederic; Kuhn, Cyrille; Ding, Yuan-Hua

    Chemical Biology & Drug Design (2007), 70 (6), 540-546CODEN: CBDDAL; ISSN:1747-0277. (Blackwell Publishing Ltd.)

    Polo-like kinase 1 is an important regulator of cell cycle progression whose over-expression is often assocd. with oncogenesis. Polo-like kinase 1 hence represents an attractive target for cancer intervention. BI 2536 (Boehringer Ingelheim, Ingelheim, Germany), a Polo-like kinase 1 inhibitor currently in clin. trials, exhibits nanomolar potency against Polo-like kinase isoforms and high selectivity against other kinases. The authors have previously published the crystal structures of the Polo-like kinase 1 domain in complex with AMPPNP and an Aurora A inhibitor. In this work, the authors present the cocrystal structure of Polo-like kinase 1 with BI 2536. The structure, in combination with selectivity data for BI 2536 and related compds., illustrates important features for potency and selectivity. In particular, the authors show that the methoxy group of BI 2536 is an important specificity determinant against non-Polo-like kinases by taking advantage of a small pocket generated by Leu 132 in the hinge region of Polo-like kinase 1. The work presented here provides a framework for structure-based drug design of Polo-like kinase 1-specific inhibitors.

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    Blake, J. F.; Burkard, M.; Chan, J.; Chen, H.; Chou, K.-J.; Diaz, D.; Dudley, D. A.; Gaudino, J. J.; Gould, S. E.; Grina, J.; Hunsaker, T.; Liu, L.; Martinson, M.; Moreno, D.; Mueller, L.; Orr, C.; Pacheco, P.; Qin, A.; Rasor, K.; Ren, L.; Robarge, K.; Shahidi-Latham, S.; Stults, J.; Sullivan, F.; Wang, W.; Yin, J.; Zhou, A.; Belvin, M.; Merchant, M.; Moffat, J.; Schwarz, J. B. Discovery of (S)-1-(1-(4-Chloro-3-Fluorophenyl)-2-Hydroxyethyl)-4-(2-((1-Methyl-1H-Pyrazol-5-Yl)Amino)Pyrimidin-4-Yl)Pyridin-2(1H)-One (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development. J. Med. Chem. 2016, 59, 5650– 5660,  DOI: 10.1021/acs.jmedchem.6b00389

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    Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development

    Blake, James F.; Burkard, Michael; Chan, Jocelyn; Chen, Huifen; Chou, Kang-Jye; Diaz, Dolores; Dudley, Danette A.; Gaudino, John J.; Gould, Stephen E.; Grina, Jonas; Hunsaker, Thomas; Liu, Lichuan; Martinson, Matthew; Moreno, David; Mueller, Lars; Orr, Christine; Pacheco, Patricia; Qin, Ann; Rasor, Kevin; Ren, Li; Robarge, Kirk; Shahidi-Latham, Sheerin; Stults, Jeffrey; Sullivan, Francis; Wang, Weiru; Yin, Jianping; Zhou, Aihe; Belvin, Marcia; Merchant, Mark; Moffat, John; Schwarz, Jacob B.

    Journal of Medicinal Chemistry (2016), 59 (12), 5650-5660CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clin., resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small mol. inhibitor selective for ERK kinase activity.

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44. 44

    Johnson, T. W.; Richardson, P. F.; Bailey, S.; Brooun, A.; Burke, B. J.; Collins, M. R.; Cui, J. J.; Deal, J. G.; Deng, Y.; Dinh, D.; Engstrom, L. D.; He, M.; Hoffman, J.; Hoffman, R. L.; Huang, Q.; Kania, R. S.; Kath, J. C.; Lam, H.; Lam, J. L.; Le, P. T.; Lingardo, L.; Liu, W.; McTigue, M.; Palmer, C. L.; Sach, N. W.; Smeal, T.; Smith, G. L.; Stewart, A. E.; Timofeevski, S.; Zhu, H.; Zhu, J.; Zou, H. Y.; Edwards, M. P. Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro- 2H −8,4-(Metheno)Pyrazolo[4,3-h][2,5,11]-Benzoxadiazacyclotetradecine-3-Carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-Ros. J. Med. Chem. 2014, 57, 4720– 4744,  DOI: 10.1021/jm500261q

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    Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

    Johnson, Ted W.; Richardson, Paul F.; Bailey, Simon; Brooun, Alexei; Burke, Benjamin J.; Collins, Michael R.; Cui, J. Jean; Deal, Judith G.; Deng, Ya-Li; Dinh, Dac; Engstrom, Lars D.; He, Mingying; Hoffman, Jacqui; Hoffman, Robert L.; Huang, Qinhua; Kania, Robert S.; Kath, John C.; Lam, Hieu; Lam, Justine L.; Le, Phuong T.; Lingardo, Laura; Liu, Wei; McTigue, Michele; Palmer, Cynthia L.; Sach, Neal W.; Smeal, Tod; Smith, Graham L.; Stewart, Albert E.; Timofeevski, Sergei; Zhu, Huichun; Zhu, Jinjiang; Zou, Helen Y.; Edwards, Martin P.

    Journal of Medicinal Chemistry (2014), 57 (11), 4720-4744CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-pos. non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addn., some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and phys.-property-based optimization, highly potent macrocyclic ALK inhibitors were prepd. with good absorption, distribution, metab., and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clin. reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

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45. 45

    Tan, L.; Akahane, K.; McNally, R.; Reyskens, K. M. S. E.; Ficarro, S. B.; Liu, S.; Herter-Sprie, G. S.; Koyama, S.; Pattison, M. J.; Labella, K.; Johannessen, L.; Akbay, E. A.; Wong, K.-K.; Frank, D. A.; Marto, J. A.; Look, T. A.; Arthur, J. S. C.; Eck, M. J.; Gray, N. S. Development of Selective Covalent Janus Kinase 3 Inhibitors. J. Med. Chem. 2015, 58, 6589– 6606,  DOI: 10.1021/acs.jmedchem.5b00710

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    Development of Selective Covalent Janus Kinase 3 Inhibitors

    Tan, Li; Akahane, Koshi; McNally, Randall; Reyskens, Kathleen M. S. E.; Ficarro, Scott B.; Liu, Suhu; Herter-Sprie, Grit S.; Koyama, Shohei; Pattison, Michael J.; Labella, Katherine; Johannessen, Liv; Akbay, Esra A.; Wong, Kwok-Kin; Frank, David A.; Marto, Jarrod A.; Look, Thomas A.; Arthur, J. Simon C.; Eck, Michael J.; Gray, Nathanael S.

    Journal of Medicinal Chemistry (2015), 58 (16), 6589-6606CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a crit. immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently obsd. in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacol. probes and as clin. drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochem. and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compds. 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compd. 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacol. interrogate JAK3-dependent biol.

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46. 46

    Smilkstein, M.; Sriwilaijaroen, N.; Kelly, J. X.; Wilairat, P.; Riscoe, M. Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening. Antimicrob. Agents Chemother. 2004, 48, 1803– 1806,  DOI: 10.1128/AAC.48.5.1803-1806.2004

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    Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening

    Smilkstein, Martin; Sriwilaijaroen, Nongluk; Kelly, Jane Xu; Wilairat, Prapon; Riscoe, Michael

    Antimicrobial Agents and Chemotherapy (2004), 48 (5), 1803-1806CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)

    Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay for use in antimalarial drug screening. Parasite growth is detd. by using SYBR Green 1, a dye with marked fluorescence enhancement upon contact with Plasmodium DNA. A side-by-side comparison of this fluorescence assay and a std. radioisotopic method was performed by testing known antimalarial agents against Plasmodium falciparum strain D6. Both assay methods were used to det. the effective concn. of drug that resulted in a 50% redn. in the obsd. counts (EC50) after 48 h of parasite growth in the presence of each drug. The EC50s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-.vepsiln.-(N,N-diethylamino)-amyloxyanthone were similar or identical by both techniques. The results obtained with this new fluorescence assay suggest that it may be an ideal method for high-throughput antimalarial drug screening.

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47. 47

    Rakotoarivelo, N. V.; Perio, P.; Najahi, E.; Nepveu, F. Interaction between Antimalarial 2-Aryl-3H-Indol-3-One Derivatives and Human Serum Albumin. J. Phys. Chem. B 2014, 118, 13477– 13485,  DOI: 10.1021/jp507569e

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    Interaction between Antimalarial 2-Aryl-3H-indol-3-one Derivatives and Human Serum Albumin

    Rakotoarivelo, Nambinina V.; Perio, Pierre; Najahi, Ennaji; Nepveu, Francoise

    Journal of Physical Chemistry B (2014), 118 (47), 13477-13485CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Binding of drugs to plasma proteins, such as albumin, is a major factor which dets. their pharmacokinetics and pharmacol. effects. Therefore, the interactions between human serum albumin (HSA) and four antimalarial compds. selected in the 2-aryl-3H-indol-3-one series have been investigated using UV-visible, fluorescence and CD spectroscopies. Compds. produced a static quenching of the intrinsic fluorescence of HSA. The thermodn. parameters have shown that the binding reaction is endothermic for three compds. while exothermic for the 2-phenyl-3H-indol-3-one, 3. The interaction is entropically driven with predominant hydrophobic forces with binding affinities of the order of 104 M-1. The highest binding const. is obsd. for 3 (Kλ=280nm = 4.53 × 104 M-1) which is also the less active compd. against Plasmodium falciparum. Synchronous fluorescence gave qual. information on the conformational changes of HSA while quant. data were obtained with CD. Displacement expts. with site markers indicated that drugs bind to HSA at site I (subdomain IIA). In addn., the apparent binding const. and the binding site no. were calcd. in the presence of different ions.

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