ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity

View Author Information
Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan
§ Eisai, Inc., 4 Corporate Drive, Andover, Massachusetts 01810, United States
*Tel: 617-500-0691. E-mail: [email protected]
Cite this: ACS Med. Chem. Lett. 2015, 6, 5, 491–495
Publication Date (Web):March 4, 2015
https://doi.org/10.1021/acsmedchemlett.5b00037

Copyright © 2015 American Chemical Society. This publication is licensed under these Terms of Use.

  • Open Access
  • Editors Choice

Article Views

7505

Altmetric

-

Citations

LEARN ABOUT THESE METRICS
PDF (1 MB)
Supporting Info (1)»

Abstract

Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.

Inhibitors of Enhancer of Zeste Homolog 2 (EZH2) target the catalytic center of a multiprotein complex known as polycomb repressive complex 2 (PRC2). The PRC2 complex is responsible for methylating a specific histone lysine referred to as H3K27. (1, 2) In multiple human cancers, hyper-trimethylation of H3K27 results in the aberrant silencing of genes that otherwise control cell proliferation and induce differentiation. (3) Moreover, genetic alterations of PRC2 components have been documented in both hematologic and solid tumors. (4) For instance, EZH2 change-of-function mutations (affecting residues Y646, A682, and A692) are found in subsets of B cell non-Hodgkin lymphoma (NHL) where they confer an oncogenic dependency on EZH2. Hence, EZH2 mutant-bearing, diffuse large B cell lymphoma (DLBCL) cell lines can be effectively killed by EZH2 inhibitors in vitro and in vivo. (5) Intriguingly, we have also shown that sensitivity to EZH2 inhibition in EZH2 mutant DLBCL cell lines of germinal center origin (GCB) can be enhanced by combination with prednisone, the glucocorticoid-agonist component of the standard chemotherapy regimen CHOP; this sensitivity can be extended to EZH2 wild-type GCB and to inhibitor-refractory, EZH2 mutant GCB cell lines. (6) In stark contrast, myeloid malignancies and T cell leukemia (7) bear mutations in EZH2 and other PRC2 components that lead to a loss of function of the complex, thus exemplifying the biological complexity of the role of H3K27 methylation in cancers. (8) As a result of this complexity and the importance of EZH2 as a therapeutic target for specific human cancers, research in the field has continued to expand in recent years thereby driving the need for well-characterized chemical probes.

As we have described previously, the pyridone-benzamide core represents a highly optimized feature for binding to EZH2 in a SAM-competitive manner. This is a common feature in known indazole EZH2 inhibitors (e.g., EPZ005687, (9)UNC-1999 (10)), indole EZH2 inhibitors (e.g., GSK-126, (11)EI1, (12)CPI-169 (13)) and EPZ-6438, our EZH2 inhibitor presently undergoing clinical trials. (4) In pyridone-containing EZH2 inhibitors, pyridone oxidation is a common site of metabolism. Recently, there have been a series of published reports that propose a pyridone-replacement chemotype, 4-amino-2,2′,6,6′-tetramethyl-piperidine, as one means to avoid this issue and to expand the breadth of EZH2 inhibitors. (14, 15) To date, however, compounds with this novel substitution have not demonstrated potency equivalent to pyridone-containing inhibitors and have not reported in vivo activity. Because the pyridone plays such a role in binding and therefore potency, our continued research in this area has focused on modifications to other regions of our chemical scaffold to further investigate the impact on in vivo activity. What is needed today are potent, bioavailable tool compounds that can be made widely available to the greater research community to augment our collective understanding of the role of EZH2 in pathobiology. Herein we describe the discovery, characterization, and in vivo profile of such a chemical probe, EPZ011989.

Figure 1

Figure 1. Representative reported EZH2 inhibitors.

Figure 2

Figure 2. SAR affords a potent, stable EZH2 inhibitor.

N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3-morpholinoprop-1-yn-1-yl)benzamide (EPZ011989, Figure 2) was discovered through modification of the pyran substituent in EPZ-6438 (Figure 1). In this position, a trans-N,N-dimethylcyclohexylamine substituent appears to maintain biochemical activity, but when combined with the morpholine side-chain, the cellular activity of the resulting dibasic compound is negatively impacted. A series of compounds were designed to attenuate the pKa of the amine components, and a balance of properties and potency was achieved through the addition of a methoxyethyl group to the cyclohexylamine (ca. pKa = 9.8) (16) combined with the replacement of the second benzene ring in EPZ-6438 with an acetylene linker to modify the adjacent morpholine (ca. pKa = 5.7).

Table 1. EPZ011989 in Vitro Data Summary
propertyanalysisunitsEPZ011989
EZH2 activitybiochemical KinM<3 (WT) <3 (Y646)
ELISA H3K27me3 IC50anM94 ± 48 (n = 20)
liver microsome clearancescaled microsomal clearancebmL/min/kg (%Eh)chuman6 ± 0.5(29)
rat<10(<14)
mouse<10(<11)
plasma protein bindingequilibrium dialysispercent unboundhuman97 ± 3
rat91 ± 6
mouse80 ± 11
LCC11d proliferation WSU-DLCL2nM208 ± 75 (n = 4)
predicted efficacious plasma exposurednM (ng/mL)human214(130)
rat223(135)
mouse260(158)
a

Enzyme-linked immunoassay measure of cellular methyl mark reduction.

b

Scaled according to the well-stirred liver model.

c

Percent hepatic extraction.

d

Plasma protein binding corrected LCC.

These adjustments led to a compound, EPZ011989, that equipotently inhibits mutant and wild-type EZH2 with an inhibition constant (Ki) of <3 nM. EPZ011989 is also a specific EZH2 inhibitor with a >15-fold selectivity over EZH1 and >3000-fold selectivity relative to the Ki of 20 other histone methyltransferases (HMTs) tested. As evidenced by the human and rat liver microsomal turnover (HLM and RLM respectively, Figure 2), EPZ011989 also exhibits metabolic stability (Table 1). Furthermore, EPZ011989 reduces cellular H3K27 methylation in the Y641F, mutant-bearing human lymphoma cell line, WSU-DLCL2, with an IC50 below 100 nM. This functional response translates to activity in a long-term proliferation assay where EPZ011989 demonstrates an average lowest cytotoxic concentration (LCC) in WSU-DLCL2 cells of 208 nM (Figure 3).

Figure 3

Figure 3. Effect of EPZ011989 concentration on the proliferation of WSU-DLCL2 cells in culture over an 11-day period.

The LCC parameter, when corrected for plasma protein-binding, predicts an efficacious plasma level in mouse for EPZ011989 of 158 ng/mL. The LCC-predicted exposure was used as a benchmark to enable the selection of doses bracketing this value for in vivo studies. The pharmacokinetics in SCID mice following oral administration of 125, 250, 500, and 1000 mg/kg indicated that the 1000 mg/kg dose provided coverage over the LCC for 24 h, while the 250 and 500 mg/kg doses provided coverage over this value for approximately 8 h (Figure 4). This confirmed that, with appropriate formulation, sustained exposure above the LCC could be achieved in vivo.

Figure 4

Figure 4. Single dose PK in SCID mice following oral administration of 125, 250, 500, and 1000 mg/kg dosed as suspensions in 0.5% w/v methyl cellulose and 0.1% Tween-80 acidified with 1 mol equiv of HCl. LCC predicted efficacious plasma level for compound EPZ011989 (158 ng/mL) is shown by a horizontal, dashed line.

Figure 5

Figure 5. (a) Pharmacokinetic analysis of day 7 plasma samples for EPZ011989. (b) Pharmacodynamic analysis of histone methyl mark in bone marrow tissue at day 7 of dosing EPZ011989.

On the basis of the preliminary PK results, we conducted a 7-day PK study with pharmacodynamic (PD) measurement of H3K27 methylation in bone marrow at 125, 250, 500, 750, and 1000 mg/kg dosed twice-daily (BID). All of the doses were well tolerated for the length of the study. The results from this experiment are shown in Figure 5, where the trough exposure represents the Cmin at 12 h after the first dose on day 7 of test article administration. The dose of EPZ011989 that achieves complete coverage over the predicted efficacious plasma level was determined to be 500 mg/kg BID (Figure 5a). The exposures at 500 mg/kg BID (mean Cmin = 150 ng/mL) correspond well with the above PK experiment and with the PD results in bone marrow, where we observed complete ablation of the methyl mark by the end of day 7 (Figure 5b).

The above results demonstrate that formulation of the free base of EPZ011989 in HCl-acidified vehicle was suitable to complete target engagement proof-of-concept studies. After completion of this initial PK/PD study, we performed a salt screen, which identified the d-tartrate salt (DTAL), an amorphous solid with low hygroscopicity, as an alternative for future work. We conducted a rat PK experiment at 30, 100, and 300 mg/kg (Table 2) and found that this optimized salt form provided sustained oral exposure over the rat predicted efficacious plasma exposure (135 ng/mL) for approximately 10 h after a single dose (Figure 6).

Table 2. Summary of Rat PK for EPZ011989
EPZ011989 Rat PK
dose
(mg/kg)
routet1/2
(h)
tmax
(h)
Cmax
(ng/mL)
AUCinf
(h·ng/mL)
time above
LCC (h)
30 p.o.4.722409704
100 p.o.3.92.7160056008
300 p.o.3.72.729001000010

Figure 6

Figure 6. PK after oral dosing of EPZ011989 DTAL at doses of 30, 100, and 300 mg/kg.

To demonstrate further the utility of EPZ011989 as an in vivo tool compound, we evaluated the antitumor activity of the optimized d-tartrate salt form in the treatment of subcutaneous EZH2 mutant KARPAS-422 human DLBCL xenografts. Homogenous suspensions of 250 and 500 mg/kg in 0.5% methyl cellulose and 0.1% Tween-80 were dosed orally to implanted SCID mice for 21 days, BID. On the basis of the PD study, we expected to see tumor regression with the 500 mg/kg dose; however, EPZ011989 administration induced significant tumor regression at both doses, with nominal effect on mean body weights over the course of the study period (Figure 7). Evaluation of PD in tumor samples on day 7 demonstrated robust H3K27 methyl mark reduction for EPZ011989 at the 250 and 500 mg/kg dose over the 12 h time-course (Figure 8). Notably, the exposure for EPZ011989 at 3 h postdose is an order of magnitude higher in this experiment, using the DTAL salt, than for the corresponding dose in the PK/PD study (Figure 9). As a result, at a dose of 250 mg/kg, EPZ011989 remains over the predicted efficacious plasma levels for a minimum of 6 h, though not for the full 12 h time interval. Examination of the data in Figure 8 reveals that, even though plasma exposure does not remain over the LCC, tumor methyl mark levels do not rebound during the dosing interval at 500 nor 250 mg/kg. This suggests that the observed efficacious exposure of EPZ011989 required for tumor growth inhibition is even lower than the level predicted by the LCC and that persistent methyl mark inhibition likely accounts for the resultant antitumor activity at lower exposure. Additional PK and xenograft studies are underway to see if this observation with EPZ011989 holds in the exploration of an expanded set of cancer types associated with EZH2 mutation and dysfunction.

Figure 7

Figure 7. Robust tumor growth inhibition seen at 250 and 500 mg/kg BID EPZ011989.

Figure 8

Figure 8. Methyl mark reduction observed in tumor tissue over time on day 7 of EPZ011989 administration.

Figure 9

Figure 9. Total and free plasma exposure time courses for EPZ011989 in the KARPAS-422 xenograft study. Values measured postdose on day 7 of 21.

Through SAR studies on the pyridone-benzamide scaffold we have discovered an in vivo tool compound with which to further the study of the role of the PRC2 complex in biology and in preclinical models of disease. We have characterized EPZ011989, a compound with oral exposure and metabolic stability that is able to elicit robust methyl mark inhibition and antitumor activity. The PK/PD and in vivo activity data for this compound were highlighted to enable collaborative research in the field. Samples of EPZ011989 can be made available upon request.

Supporting Information

ARTICLE SECTIONS
Jump To

Detailed biological assay information, and procedures and characterization data for the synthesis of EPZ011989. This material is available free of charge via the Internet at http://pubs.acs.org.

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

ARTICLE SECTIONS
Jump To

  • Corresponding Author
    • John E. Campbell - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States Email: [email protected]
  • Authors
    • Kevin W. Kuntz - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Sarah K. Knutson - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Natalie M. Warholic - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Heike Keilhack - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Tim J. Wigle - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Alejandra Raimondi - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Christine R. Klaus - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Nathalie Rioux - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Akira Yokoi - Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan
    • Satoshi Kawano - Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan
    • Yukinori Minoshima - Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan
    • Hyeong-Wook Choi - Eisai, Inc., 4 Corporate Drive, Andover, Massachusetts 01810, United States
    • Margaret Porter Scott - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Nigel J. Waters - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Jesse J. Smith - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Richard Chesworth - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Mikel P. Moyer - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
    • Robert A. Copeland - Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
  • Notes
    The authors declare the following competing financial interest(s): J.E.C., K.W.K., S.K.K., N.M.W., H.K., T.J.W., A.R., C.R.K., N.R., M.P.S., N.J.W., J.J.S., R.C., M.P.M., and R.A.C. have ownership interest (including patents) in Epizyme.

Biography

ARTICLE SECTIONS
Jump To

John E. Campbell

John E. Campbell received his Ph.D. in Organic Chemistry from the University of Wisconsin−Madison in 2003 for the total synthesis of unnatural macrocycle ionophores under the supervision of Steve D. Burke. After returning to the East Coast for postdoctoral training in transition metal catalysis at Boston College with Amir H. Hoveyda, he entered the pharmaceutical industry as a bench chemist at Sepracor, Inc. (now Sunovion), developing small molecule candidates for the treatment of depression and schizophrenia. After 6 years and participating in three Investigational New Drugs (INDs), John moved to Epizyme where he now holds the title of Principal Scientist, and his research focus centers on the development of small molecule inhibitors of chromatin-modifying enzymes, searching for therapeutics for genetically defined cancers.

Acknowledgment

ARTICLE SECTIONS
Jump To

We thank Rahul Nagawade for his contribution to the synthesis of EPZ011989.

ABBREVIATIONS

ARTICLE SECTIONS
Jump To

EZH2

enhancer of zeste Homolog 2

PRC2

polycomb repressive complex 2

H3K27

histone 3 lysine 27

NHL

non-Hodgkin lymphoma

DLBCL

diffuse large B cell lymphoma

SAR

structure–activity relationship

%Eh

percent hepatic extraction

LCC

lowest cytotoxic concentration

HMTs

histone methyltransferases

HLM

human liver microsomes

RLM

rat liver microsomes

SCID

severe combined immune deficiency

BID

twice-daily dosing

PK

pharmacokinetics

PD

pharmacodynamics

DTAL

d-tartrate salt

p.o.

oral dosing

SEM

standard error of the mean

H3K27me3

histone 3 lysine 27 trimethyl

References

ARTICLE SECTIONS
Jump To

This article references 16 other publications.

  1. 1
    Kuzmichev, A.; Nishioka, K.; Erdjument-Bromage, H.; Tempst, P.; Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein Genes Dev. 2002, 16, 2893 2905
  2. 2
    Cao, R.; Wang, L.; Xia, L.; Erdjument-Bromage, H.; Tempst, P.; Jones, R. S.; Zhang, Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing Science 2002, 298, 1039 1043
  3. 3
    Simon, J. A.; Lange, C. A. Roles of the EZH2 Histone Methyltransferase in Cancer Epigenetics Mutat. Res. 2008, 647, 21 29
  4. 4
    Knutson, S. K.; Warholic, N. M.; Wigle, T. J.; Klaus, C. R.; Allain, C. J.; Raimondi, A.; Porter-Scott, M.; Chesworth, R.; Moyer, M. P.; Copeland, R. A.; Richon, V. M.; Pollock, R. M.; Kuntz, K. W.; Keilhack, H. Durable Tumor Regression in Genetically Altered Malignant Rhabdoid Tumors by Inhibition of Methyltransferase EZH2 Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 7922 7927
  5. 5
    Sneeringer, C. J.; Porter-Scott, M.; Kuntz, K. W.; Knutson, S. K.; Pollock, R. M.; Richon, V. R.; Copeland, R. A. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (HEK27) in human B cell Lymphomas Proc. Natl. Acad. Sci. U.S.A. 2011, 107, 20980 20985
  6. 6
    Knutson, S. K.; Warholic, N. M.; Johnston, L. D.; Klaus, C. R.; Wigle, T. J.; Iwanowicz, D.; Littlefield, B. A.; Porter-Scott, M.; Smith, J.; Moyer, M. P.; Copeland, R. A.; Pollock, R. M.; Kuntz, K. W.; Raimondi, A.; Keilhack, H. Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocoericoid Receptor Agonists in Models of Germinal Center Non-Hodgekin Lymphomas PLoS One 2014, 9, e111840
  7. 7
    Ntziachristos, P.; Tsirigos, A.; Van Vlierberghe, P.; Nedjic, J.; Trimarchi, T.; Sol Flaherty, M.; Ferres-Marco, D.; da Ros, V.; Tang, Z.; Siegle, J.; Asp, P.; Hadler, M.; Rigo, I.; De Keersmaecker, K.; Patel, J.; Huynh, T.; Utro, F.; Poglio, S.; Samon, J. B.; Paietta, E.; Recevskis, J.; Rowe, J. M.; Rabadan, R.; Levine, R. L.; Brown, S.; Pflumio, F.; Dominguez, M.; Ferrando, A.; Aifantis, I. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia Nat. Med. 2012, 18, 298 303
  8. 8
    Wang, S.; Robertson, G. P.; Zhu, J. A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers Gene 2004, 343, 69 78
  9. 9
    Knutson, S. K.; Wigle, T. J.; Warholic, N. M.; Sneeringer, C. J.; Allain, C. J.; Klaus, C. R.; Sacks, J. D.; Raimondi, A.; Majer, C. R.; Song, J.; Porter-Scott, M.; Jin, L.; Smith, J. J.; Olhava, E. J.; Chesworth, R.; Moyer, M.; Richon, V. M.; Copeland, R. A.; Keilhack, H.; Pollock, R. M.; Kuntz, K. W. A Selective Inhibitor of EZH2 blocks H3K27 methylation and Kills Mutant Lymphoma Cells Nat. Chem. Biol. 2012, 8, 890 896
  10. 10
    Konze, K. D.; Ma, A.; Li, F.; Barsyte-Lovejoy, D.; Parton, T.; MacNevin, C. J.; Liu, F.; Gao, C.; Huang, X.-P.; Kuznetsova, E.; Rougie, M.; Jiang, A.; Patterden, S. G.; Norris, J. L.; James, L. I.; Roth, B. L.; Brown, P. J.; Frye, S. V.; Arrowsmith, C. H.; Hahn, K. M.; Wang, G. G.; Vedadi, M.; Jin, J. An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1 ACS Chem. Biol. 2013, 8, 1324 1334
  11. 11
    Verma, S. K.; Tian, X.; LaFrance, L. V.; Duquenne, C.; Suarez, D. P.; Newlander, K. A.; Romeril, S. P.; Burgess, J. L.; Grant, S. W.; Brackley, J. A.; Graves, A. P.; Scherzer, D. A.; Shu, A.; Thompson, C.; Ott, H. M.; Van Aller, G. S.; Machutta, C. A.; Diaz, E.; Jiang, Y.; Johnson, N. W.; Knight, S. D.; Kruger, R. G.; McCabe, M. T.; Dhanak, D.; Tummino, P. J.; Creasy, C. L.; Miller, W. H. Identification of Potent, Selective Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2 ACS Med. Chem. Lett. 2012, 3, 1091 1096
  12. 12
    Qi, W.; Chan, H.; Teng, L.; Li, L.; Chuai, S.; Zhang, R.; Zeng, J.; Li, M.; Fan, H.; Lin, Y.; Gu, J.; Ardayfio, O.; Zhang, J.-H.; Yan, X.; Fang, J.; Mi, Y.; Zhang, M.; Zhao, T.; Feng, G.; Chen, Z.; Li, G.; Ynag, T.; Zhao, K.; Liu, X.; Yu, Z.; Lu, C. X.; Atadja, P.; Li, E. Selective inhibition of EZH2 by a small molecule inhibitor blocks tumor cell proliferation Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 21360 21365
  13. 13
    Bradley, W. D.; Arora, S.; Busby, J.; Balasubramanian, S.; Gehling, V.; Nasveschuk, C. G.; Vaswani, R. G.; Yuan, C.-C.; Hatton, C.; Zhao, F.; Williamson, K. E.; Iyer, P.; Méndez, J.; Campbell, R.; Cantone, N.; Garapaty-Rao, S.; Audia, J.; Cook, A. S.; Dakin, L. A.; Albrecht, B. K.; Harmange, J.-C.; Daniels, D. L.; Cummings, R. T.; Bryant, B. M.; Normant, E.; Trojer, P. EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation Chem. Biol. 2014, 21, 1463 1475
  14. 14
    Garapaty-Rao, S.; Nasvechuk, C.; Gagnon, A.; Chan, E. Y.; Sandy, P.; Busby, J.; Balasubramanian, S.; Campbell, R.; Zhao, F.; Bergeron, L.; Audia, J. E.; Albrecht, B. K.; Harmange, J.-C.; Cummings, R.; Trojer, P. Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth Chem. Biol. 2013, 20, 1329 1339
  15. 15
    Nasveschuk, C. G.; Gagnon, A.; Garapaty-Rao, S.; Balasubramanian, S.; Campbell, R.; Lee, C.; Zhao, F.; Bergeron, L.; Cummings, R.; Trojer, P.; Audia, J. E.; Albrecht, B. K.; Harmange, J.-C. P. Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2 ACS Med. Chem. Lett. 2014, 5, 378 383
  16. 16
    As calculated using ChemAxon JChem for Excel software. http://www.chemaxon.com/conf/Calculating_pKa_values_of_small_and_large_molecules.pdf.

Cited By

ARTICLE SECTIONS
Jump To

This article is cited by 102 publications.

  1. Mingxing Ye, Mengyuan Hou, Yahao Wang, Xingxing Ma, Kai Yang, Qiuling Song. Arylation of Terminal Alkynes: Transition-Metal-Free Sonogashira-Type Coupling for the Construction of C(sp)–C(sp2) Bonds. Organic Letters 2023, 25 (10) , 1787-1792. https://doi.org/10.1021/acs.orglett.3c00586
  2. Juan Xia, Jingyi Li, Lei Tian, Xiaodong Ren, Chang Liu, Chengyuan Liang. Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure–Activity Relationships Insights and Evolution Prospects. Journal of Medicinal Chemistry 2022, 65 (10) , 7016-7043. https://doi.org/10.1021/acs.jmedchem.2c00047
  3. M. Cynthia Martin, Guihua Zeng, Jindan Yu, Gary E. Schiltz. Small Molecule Approaches for Targeting the Polycomb Repressive Complex 2 (PRC2) in Cancer. Journal of Medicinal Chemistry 2020, 63 (24) , 15344-15370. https://doi.org/10.1021/acs.jmedchem.0c01344
  4. Babita Kaundal, Anup K. Srivastava, Atul Dev, Soni Jignesh Mohanbhai, Surajit Karmakar, Subhasree Roy Choudhury. Nanoformulation of EPZ011989 Attenuates EZH2–c-Myb Epigenetic Interaction by Proteasomal Degradation in Acute Myeloid Leukemia. Molecular Pharmaceutics 2020, 17 (2) , 604-621. https://doi.org/10.1021/acs.molpharmaceut.9b01071
  5. Jon A. Read, Jonathan Tart, Philip B. Rawlins, Clare Gregson, Karen Jones, Ning Gao, Xiahui Zhu, Ron Tomlinson, Erin Code, Tony Cheung, Huawei Chen, Sameer P. Kawatkar, Andy Bloecher, Sharan Bagal, Daniel H. O’Donovan, James Robinson. Rapid Identification of Novel Allosteric PRC2 Inhibitors. ACS Chemical Biology 2019, 14 (10) , 2134-2140. https://doi.org/10.1021/acschembio.9b00468
  6. Lihai Yu, Nikola Despotovic, Michael S. Kovacs, Christopher L. Pin, Leonard G. Luyt. 18F-Labeled PET Probe Targeting Enhancer of Zeste Homologue 2 (EZH2) for Cancer Imaging. ACS Medicinal Chemistry Letters 2019, 10 (3) , 334-340. https://doi.org/10.1021/acsmedchemlett.8b00613
  7. H. Ümit Kaniskan, Michael L. Martini, and Jian Jin . Inhibitors of Protein Methyltransferases and Demethylases. Chemical Reviews 2018, 118 (3) , 989-1068. https://doi.org/10.1021/acs.chemrev.6b00801
  8. Biao Lu, Xiaodong Shen, Lei Zhang, Dong Liu, Caihua Zhang, Jingsong Cao, Ru Shen, Jiayin Zhang, Dan Wang, Hong Wan, Zhibin Xu, Ming-Hsun Ho, Minsheng Zhang, Lianshan Zhang, Feng He, and Weikang Tao . Discovery of EBI-2511: A Highly Potent and Orally Active EZH2 Inhibitor for the Treatment of Non-Hodgkin’s Lymphoma. ACS Medicinal Chemistry Letters 2018, 9 (2) , 98-102. https://doi.org/10.1021/acsmedchemlett.7b00437
  9. Kimberly D. Barnash, Juliana The, Jacqueline L. Norris-Drouin, Stephanie H. Cholensky, Beau M. Worley, Fengling Li, Jacob I. Stuckey, Peter J. Brown, Masoud Vedadi, Cheryl H. Arrowsmith, Stephen V. Frye, and Lindsey I. James . Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2. ACS Combinatorial Science 2017, 19 (3) , 161-172. https://doi.org/10.1021/acscombsci.6b00174
  10. Kyle V. Butler, Anqi Ma, Wenyu Yu, Fengling Li, Wolfram Tempel, Nicolas Babault, Fabio Pittella-Silva, Jason Shao, Junyi Wang, Minkui Luo, Masoud Vedadi, Peter J. Brown, Cheryl H. Arrowsmith, and Jian Jin . Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase. Journal of Medicinal Chemistry 2016, 59 (21) , 9881-9889. https://doi.org/10.1021/acs.jmedchem.6b01244
  11. Rishi G. Vaswani, Victor S. Gehling, Les A. Dakin, Andrew S. Cook, Christopher G. Nasveschuk, Martin Duplessis, Priyadarshini Iyer, Srividya Balasubramanian, Feng Zhao, Andrew C. Good, Robert Campbell, Christina Lee, Nico Cantone, Richard T. Cummings, Emmanuel Normant, Steven F. Bellon, Brian K. Albrecht, Jean-Christophe Harmange, Patrick Trojer, James E. Audia, Ying Zhang, Neil Justin, Shuyang Chen, Jon R. Wilson, and Steven J. Gamblin . Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas. Journal of Medicinal Chemistry 2016, 59 (21) , 9928-9941. https://doi.org/10.1021/acs.jmedchem.6b01315
  12. Xiaobao Yang, Fengling Li, Kyle D. Konze, Jamel Meslamani, Anqi Ma, Peter J. Brown, Ming-Ming Zhou, Cheryl H. Arrowsmith, H. Ümit Kaniskan, Masoud Vedadi, and Jian Jin . Structure–Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors. Journal of Medicinal Chemistry 2016, 59 (16) , 7617-7633. https://doi.org/10.1021/acs.jmedchem.6b00855
  13. Yuxi Cheng, Zhengzheng Song, Xiaodan Fang, Zhangui Tang. Polycomb repressive complex 2 and its core component EZH2: potential targeted therapeutic strategies for head and neck squamous cell carcinoma. Clinical Epigenetics 2024, 16 (1) https://doi.org/10.1186/s13148-024-01666-2
  14. Yun Chen, Hongyan Zhu, Yi Luo, Shuangmei Tong, Yan Liu. EZH2: The roles in targeted therapy and mechanisms of resistance in breast cancer. Biomedicine & Pharmacotherapy 2024, 175 , 116624. https://doi.org/10.1016/j.biopha.2024.116624
  15. Sydney Fobare, Ola A. Elgamal, Mark Wunderlich, Emily Stahl, Abeera Mehmood, Casie Furby, James R. Lerma, Thomas M. Sesterhenn, Jianmin Pan, Jayesh Rai, Megan E. Johnstone, Amina Abdul-Aziz, Mariah L. Johnson, Shesh N. Rai, John C. Byrd, Erin Hertlein. Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia. Cancers 2024, 16 (3) , 569. https://doi.org/10.3390/cancers16030569
  16. Jayden Sterling, Jennifer R. Baker, Adam McCluskey, Lenka Munoz. Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research. Nature Communications 2023, 14 (1) https://doi.org/10.1038/s41467-023-38952-1
  17. Nur Aziz, Yo Han Hong, Han Gyung Kim, Ji Hye Kim, Jae Youl Cho. Tumor-suppressive functions of protein lysine methyltransferases. Experimental & Molecular Medicine 2023, 55 (12) , 2475-2497. https://doi.org/10.1038/s12276-023-01117-7
  18. Min Gao, Yongwen Li, Peijun Cao, Hongyu Liu, Jun Chen, Shirong Kang. Exploring the therapeutic potential of targeting polycomb repressive complex 2 in lung cancer. Frontiers in Oncology 2023, 13 https://doi.org/10.3389/fonc.2023.1216289
  19. Zijun Geng, Meiqi Chen, Qixuan Yu, Shuoxi Guo, Tianli Chen, Da Liu. Histone Modification of Colorectal Cancer by Natural Products. Pharmaceuticals 2023, 16 (8) , 1095. https://doi.org/10.3390/ph16081095
  20. Ying Li, Lei Ding, Shuang Ren, Wen Zhang, Guo-Wu Rao. Protein Lysine Methyltransferases Inhibitors. Current Medicinal Chemistry 2023, 30 (27) , 3060-3089. https://doi.org/10.2174/0929867329666220829151257
  21. Xiaojuan Yang, Lu Xu, Li Yang. Recent advances in EZH2-based dual inhibitors in the treatment of cancers. European Journal of Medicinal Chemistry 2023, 256 , 115461. https://doi.org/10.1016/j.ejmech.2023.115461
  22. Yuankai Liu, Qiong Yang. The roles of EZH2 in cancer and its inhibitors. Medical Oncology 2023, 40 (6) https://doi.org/10.1007/s12032-023-02025-6
  23. Zhaoyun Liu, Yue Jia, Chun Yang, Hui Liu, Hongli Shen, Hao Wang, Rong Fu. Study on the Effect of EZH2 Inhibitor Combined with TIGIT Monoclonal Antibody against Multiple Myeloma Cells. International Journal of Molecular Sciences 2023, 24 (10) , 8603. https://doi.org/10.3390/ijms24108603
  24. Ran An, Yu-Qing Li, Yue-Ling Lin, Fang Xu, Man-Mei Li, Zhong Liu. EZH1/2 as targets for cancer therapy. Cancer Gene Therapy 2023, 30 (2) , 221-235. https://doi.org/10.1038/s41417-022-00555-1
  25. Amit Kumar, Luni Emdad, Paul B. Fisher, Swadesh K. Das. Targeting epigenetic regulation for cancer therapy using small molecule inhibitors. 2023, 73-161. https://doi.org/10.1016/bs.acr.2023.01.001
  26. Kanto Shozu, Syuzo Kaneko, Norio Shinkai, Ai Dozen, Hirofumi Kosuge, Makoto Nakakido, Hidenori Machino, Ken Takasawa, Ken Asada, Masaaki Komatsu, Kouhei Tsumoto, Shin-Ichi Ohnuma, Ryuji Hamamoto. Repression of the PRELP gene is relieved by histone deacetylase inhibitors through acetylation of histone H2B lysine 5 in bladder cancer. Clinical Epigenetics 2022, 14 (1) https://doi.org/10.1186/s13148-022-01370-z
  27. Salisa Benjaskulluecha, Atsadang Boonmee, Thitiporn Pattarakankul, Benjawan Wongprom, Jeerameth Klomsing, Tanapat Palaga. Screening of compounds to identify novel epigenetic regulatory factors that affect innate immune memory in macrophages. Scientific Reports 2022, 12 (1) https://doi.org/10.1038/s41598-022-05929-x
  28. Ivana Samaržija, Marko Tomljanović, Renata Novak Kujundžić, Koraljka Gall Trošelj. EZH2 Inhibition and Cisplatin as a Combination Anticancer Therapy: An Overview of Preclinical Studies. Cancers 2022, 14 (19) , 4761. https://doi.org/10.3390/cancers14194761
  29. Ashley K. Gartin, Thomas C. Frost, Camille H. Cushman, Brittaney A. Leeper, Prafulla C. Gokhale, James A. DeCaprio. Merkel Cell Carcinoma Sensitivity to EZH2 Inhibition Is Mediated by SIX1 Derepression. Journal of Investigative Dermatology 2022, 142 (10) , 2783-2792.e15. https://doi.org/10.1016/j.jid.2022.03.008
  30. Parvez Khan, Jawed Akhtar Siddiqui, Shailendra Kumar Maurya, Imayavaramban Lakshmanan, Maneesh Jain, Apar Kishor Ganti, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser. Epigenetic landscape of small cell lung cancer: small image of a giant recalcitrant disease. Seminars in Cancer Biology 2022, 83 , 57-76. https://doi.org/10.1016/j.semcancer.2020.11.006
  31. Samir H. Barghout, Raquel Arminda Carvalho Machado, Dalia Barsyte-Lovejoy. Chemical biology and pharmacology of histone lysine methylation inhibitors. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 2022, 1865 (6) , 194840. https://doi.org/10.1016/j.bbagrm.2022.194840
  32. Jia Zeng, Jifa Zhang, Ying Sun, Jiaxing Wang, Changyu Ren, Souvik Banerjee, Liang Ouyang, Yuxi Wang. Targeting EZH2 for cancer therapy: From current progress to novel strategies. European Journal of Medicinal Chemistry 2022, 238 , 114419. https://doi.org/10.1016/j.ejmech.2022.114419
  33. Raffaella Catalano, Annalisa Maruca, Roberta Rocca, Pierfrancesco Tassone, Giulia Panzarella, Giosuè Costa, Francesco Ortuso, Stefano Alcaro. Identification of SET/EED Dual Binders As Innovative PRC2 Inhibitors. Future Medicinal Chemistry 2022, 14 (9) , 609-621. https://doi.org/10.4155/fmc-2022-0010
  34. Alessandra Feoli, Monica Viviano, Alessandra Cipriano, Ciro Milite, Sabrina Castellano, Gianluca Sbardella. Lysine methyltransferase inhibitors: where we are now. RSC Chemical Biology 2022, 3 (4) , 359-406. https://doi.org/10.1039/D1CB00196E
  35. Qiangsheng Zhang, Hongling Yang, Qiang Feng, Jiaying Cao, Yiqian Zhang, Lu Li, Luoting Yu. Focus on the classical and non-classical functions of EZH2: Guide the development of inhibitors and degraders. Pharmacological Research 2022, 178 , 106159. https://doi.org/10.1016/j.phrs.2022.106159
  36. Miranda Fernández-Serrano, René Winkler, Juliana C. Santos, Marguerite-Marie Le Pannérer, Marcus Buschbeck, Gaël Roué. Histone Modifications and Their Targeting in Lymphoid Malignancies. International Journal of Molecular Sciences 2022, 23 (1) , 253. https://doi.org/10.3390/ijms23010253
  37. Kunal Nepali, Jing-Ping Liou. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends. Journal of Biomedical Science 2021, 28 (1) https://doi.org/10.1186/s12929-021-00721-x
  38. Sijie Wang, Sandra C. Ordonez-Rubiano, Alisha Dhiman, Guanming Jiao, Brayden P Strohmier, Casey J Krusemark, Emily C Dykhuizen. Polycomb group proteins in cancer: multifaceted functions and strategies for modulation. NAR Cancer 2021, 3 (4) https://doi.org/10.1093/narcan/zcab039
  39. Hye Jin Nam. Autophagy Modulators in Cancer: Focus on Cancer Treatment. Life 2021, 11 (8) , 839. https://doi.org/10.3390/life11080839
  40. Sijie Wang, Aktan Alpsoy, Surbhi Sood, Sandra Carolina Ordonez‐Rubiano, Alisha Dhiman, Yixing Sun, Guanming Jiao, Casey J. Krusemark, Emily C. Dykhuizen. A Potent, Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation. ChemBioChem 2021, 22 (13) , 2335-2344. https://doi.org/10.1002/cbic.202100118
  41. Johanna A Seier, Julia Reinhardt, Kritika Saraf, Susanna S Ng, Julian P Layer, Dillon Corvino, Kristina Althoff, Frank A Giordano, Alexander Schramm, Matthias Fischer, Michael Hölzel. Druggable epigenetic suppression of interferon-induced chemokine expression linked to MYCN amplification in neuroblastoma. Journal for ImmunoTherapy of Cancer 2021, 9 (5) , e001335. https://doi.org/10.1136/jitc-2020-001335
  42. Igor L. Bado, Weijie Zhang, Jingyuan Hu, Zhan Xu, Hai Wang, Poonam Sarkar, Lucian Li, Ying-Wooi Wan, Jun Liu, William Wu, Hin Ching Lo, Ik Sun Kim, Swarnima Singh, Mahnaz Janghorban, Aaron M. Muscarella, Amit Goldstein, Purba Singh, Hyun-Hwan Jeong, Chaozhong Liu, Rachel Schiff, Shixia Huang, Matthew J. Ellis, M. Waleed Gaber, Zbigniew Gugala, Zhandong Liu, Xiang H.-F. Zhang. The bone microenvironment increases phenotypic plasticity of ER+ breast cancer cells. Developmental Cell 2021, 56 (8) , 1100-1117.e9. https://doi.org/10.1016/j.devcel.2021.03.008
  43. Aishat A. Motolani, Mengyao Sun, Matthew Martin, Steven Sun, Tao Lu. Discovery of Small Molecule Inhibitors for Histone Methyltransferases in Cancer. 2021https://doi.org/10.5772/intechopen.92830
  44. Mohammed Nadim Sardoiwala, Surajit Karmakar, Subhasree Roy Choudhury. Chitosan nanocarrier for FTY720 enhanced delivery retards Parkinson’s disease via PP2A-EzH2 signaling in vitro and ex vivo. Carbohydrate Polymers 2021, 254 , 117435. https://doi.org/10.1016/j.carbpol.2020.117435
  45. Raushan T. Kurmasheva, Stephen W. Erickson, Eric Earley, Malcolm A. Smith, Peter J. Houghton. In vivo evaluation of the EZH2 inhibitor (EPZ011989) alone or in combination with standard of care cytotoxic agents against pediatric malignant rhabdoid tumor preclinical models—A report from the Pediatric Preclinical Testing Consortium. Pediatric Blood & Cancer 2021, 68 (2) https://doi.org/10.1002/pbc.28772
  46. Ran Duan, Wenfang Du, Weijian Guo. EZH2: a novel target for cancer treatment. Journal of Hematology & Oncology 2020, 13 (1) https://doi.org/10.1186/s13045-020-00937-8
  47. Deborah L. Burkhart, Katherine L. Morel, Kristine M. Wadosky, David P. Labbé, Phillip M. Galbo, Zafardjan Dalimov, Bo Xu, Massimo Loda, Leigh Ellis. Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer. Cancer Prevention Research 2020, 13 (12) , 979-988. https://doi.org/10.1158/1940-6207.CAPR-20-0186
  48. Shiva Senthil Kumar, Satarupa Sengupta, Xiaoting Zhu, Deepak Kumar Mishra, Timothy Phoenix, Lisa Dyer, Christine Fuller, Charles B. Stevenson, Mariko DeWire, Maryam Fouladi, Rachid Drissi. Diffuse Intrinsic Pontine Glioma Cells Are Vulnerable to Mitotic Abnormalities Associated with BMI-1 Modulation. Molecular Cancer Research 2020, 18 (11) , 1711-1723. https://doi.org/10.1158/1541-7786.MCR-20-0099
  49. Mohammed Nadim Sardoiwala, Anup K. Srivastava, Babita Kaundal, Surajit Karmakar, Subhasree Roy Choudhury. Recuperative effect of metformin loaded polydopamine nanoformulation promoting EZH2 mediated proteasomal degradation of phospho-α-synuclein in Parkinson’s disease model. Nanomedicine: Nanotechnology, Biology and Medicine 2020, 24 , 102088. https://doi.org/10.1016/j.nano.2019.102088
  50. Raffaella Catalano, Roberta Rocca, Giada Juli, Giosuè Costa, Annalisa Maruca, Anna Artese, Daniele Caracciolo, Pierosandro Tagliaferri, Stefano Alcaro, Pierfrancesco Tassone, Nicola Amodio. A drug repurposing screening reveals a novel epigenetic activity of hydroxychloroquine. European Journal of Medicinal Chemistry 2019, 183 , 111715. https://doi.org/10.1016/j.ejmech.2019.111715
  51. Boheng Li, Wee-Joo Chng. EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications. Journal of Hematology & Oncology 2019, 12 (1) https://doi.org/10.1186/s13045-019-0814-6
  52. Sisi Chen, Qiang Wang, Hao Yu, Maegan L. Capitano, Sasidhar Vemula, Sarah C. Nabinger, Rui Gao, Chonghua Yao, Michihiro Kobayashi, Zhuangzhuang Geng, Aidan Fahey, Danielle Henley, Stephen Z. Liu, Sergio Barajas, Wenjie Cai, Eric R. Wolf, Baskar Ramdas, Zhigang Cai, Hongyu Gao, Na Luo, Yang Sun, Terrence N. Wong, Daniel C. Link, Yunlong Liu, H. Scott Boswell, Lindsey D. Mayo, Gang Huang, Reuben Kapur, Mervin C. Yoder, Hal E. Broxmeyer, Zhonghua Gao, Yan Liu. Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway. Nature Communications 2019, 10 (1) https://doi.org/10.1038/s41467-019-13542-2
  53. Pavel Mader, Rodrigo Mendoza-Sanchez, Aman Iqbal, Aiping Dong, Elena Dobrovetsky, Victoria B. Corless, Sean K. Liew, Scott R. Houliston, Renato Ferreira De Freitas, David Smil, Carlo C. Dela Sena, Steven Kennedy, Diego B. Diaz, Hong Wu, Ludmila Dombrovski, Abdellah Allali-Hassani, Jinrong Min, Matthieu Schapira, Masoud Vedadi, Peter J. Brown, Vijayaratnam Santhakumar, Andrei K. Yudin, Cheryl H. Arrowsmith. Identification and characterization of the first fragment hits for SETDB1 Tudor domain. Bioorganic & Medicinal Chemistry 2019, 27 (17) , 3866-3878. https://doi.org/10.1016/j.bmc.2019.07.020
  54. Adrian P. Bracken, Gerard L. Brien, C. Peter Verrijzer. Dangerous liaisons: interplay between SWI/SNF, NuRD, and Polycomb in chromatin regulation and cancer. Genes & Development 2019, 33 (15-16) , 936-959. https://doi.org/10.1101/gad.326066.119
  55. Sam C Wang, Ibrahim Nassour, Shu Xiao, Shuyuan Zhang, Xin Luo, Jeon Lee, Lin Li, Xuxu Sun, Liem H Nguyen, Jen-Chieh Chuang, Lan Peng, Scott Daigle, Jeanne Shen, Hao Zhu. SWI/SNF component ARID1A restrains pancreatic neoplasia formation. Gut 2019, 68 (7) , 1259-1270. https://doi.org/10.1136/gutjnl-2017-315490
  56. Silvia Stacchiotti, Valentina Zuco, Monica Tortoreto, Denis Cominetti, Anna Maria Frezza, Stefano Percio, Valentina Indio, Marta Barisella, Valentina Monti, Silvia Brich, Annalisa Astolfi, Chiara Colombo, Sandro Pasquali, Marco Folini, Mrinal M. Gounder, Maria A. Pantaleo, Paola Collini, Angelo Paolo Dei Tos, Paolo Giovanni Casali, Alessandro Gronchi, Nadia Zaffaroni. Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft. Cancers 2019, 11 (7) , 1015. https://doi.org/10.3390/cancers11071015
  57. Pankaj Kumar Singh. Histone methyl transferases: A class of epigenetic opportunities to counter uncontrolled cell proliferation. European Journal of Medicinal Chemistry 2019, 166 , 351-368. https://doi.org/10.1016/j.ejmech.2019.01.069
  58. Helai P. Mohammad, Olena Barbash, Caretha L. Creasy. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nature Medicine 2019, 25 (3) , 403-418. https://doi.org/10.1038/s41591-019-0376-8
  59. H. Ümit Kaniskan, Jian Jin. Selective Small‐Molecule Inhibitors of Protein Methyltransferases. 2019, 201-220. https://doi.org/10.1002/9783527809257.ch9
  60. Cameron Lindsay, Morris Kostiuk, Vincent L. Biron. Pharmacoepigenetics of EZH2 Inhibitors. 2019, 447-462. https://doi.org/10.1016/B978-0-12-813939-4.00009-7
  61. Danishuddin, Naidu Subbarao, Mohammad Faheem, Shahper Nazeer Khan. Polycomb repressive complex 2 inhibitors: emerging epigenetic modulators. Drug Discovery Today 2019, 24 (1) , 179-188. https://doi.org/10.1016/j.drudis.2018.07.002
  62. Elias Orouji, Jochen Utikal. Tackling malignant melanoma epigenetically: histone lysine methylation. Clinical Epigenetics 2018, 10 (1) https://doi.org/10.1186/s13148-018-0583-z
  63. Lu Gan, Yanan Yang, Qian Li, Yi Feng, Tianshu Liu, Weijian Guo. Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomarker Research 2018, 6 (1) https://doi.org/10.1186/s40364-018-0122-2
  64. Tomoya Hirano, Shuichi Mori, Hiroyuki Kagechika. Recent Advances in Chemical Tools for the Regulation and Study of Protein Lysine Methyltransferases. The Chemical Record 2018, 18 (12) , 1745-1759. https://doi.org/10.1002/tcr.201800034
  65. Rossella Fioravanti, Giulia Stazi, Clemens Zwergel, Sergio Valente, Antonello Mai. Six Years (2012–2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2‐Pyridone Compounds. The Chemical Record 2018, 18 (12) , 1818-1832. https://doi.org/10.1002/tcr.201800091
  66. Javier A García-Vilas, Miguel Ángel Medina. Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications. World Journal of Gastroenterology 2018, 24 (33) , 3695-3708. https://doi.org/10.3748/wjg.v24.i33.3695
  67. Laurie Herviou, Giacomo Cavalli, Jerome Moreaux. Rôle de EZH2 comme biomarqueur dans le traitement personnalisé du myélome multiple. Bulletin du Cancer 2018, 105 (9) , 804-819. https://doi.org/10.1016/j.bulcan.2018.06.003
  68. Lindsay E. Moritz, Raymond C. Trievel. Structure, mechanism, and regulation of polycomb-repressive complex 2. Journal of Biological Chemistry 2018, 293 (36) , 13805-13814. https://doi.org/10.1074/jbc.R117.800367
  69. Makoto Nakagawa, Issay Kitabayashi. Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. Cancer Science 2018, 109 (8) , 2342-2348. https://doi.org/10.1111/cas.13655
  70. Nitya Gulati, Wendy Béguelin, Lisa Giulino-Roth. Enhancer of zeste homolog 2 (EZH2) inhibitors. Leukemia & Lymphoma 2018, 59 (7) , 1574-1585. https://doi.org/10.1080/10428194.2018.1430795
  71. Bayley A. Jones, Sooryanarayana Varambally, Rebecca C. Arend. Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer. Molecular Cancer Therapeutics 2018, 17 (3) , 591-602. https://doi.org/10.1158/1535-7163.MCT-17-0437
  72. Brian Lin, Julie H. Coleman, Jesse N. Peterson, Matthew J. Zunitch, Woochan Jang, Daniel B. Herrick, James E. Schwob. Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency. Cell Stem Cell 2017, 21 (6) , 761-774.e5. https://doi.org/10.1016/j.stem.2017.09.008
  73. Remi Adelaiye-Ogala, Justin Budka, Nur P. Damayanti, Justine Arrington, Mary Ferris, Chuan-Chih Hsu, Sreenivasulu Chintala, Ashley Orillion, Kiersten Marie Miles, Li Shen, May Elbanna, Eric Ciamporcero, Sreevani Arisa, Piergiorgio Pettazzoni, Giulio F. Draetta, Mukund Seshadri, Bradley Hancock, Milan Radovich, Janaiah Kota, Michael Buck, Heike Keilhack, Brian P. McCarthy, Scott A. Persohn, Paul R. Territo, Yong Zang, Joseph Irudayaraj, W. Andy Tao, Peter Hollenhorst, Roberto Pili. EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming. Cancer Research 2017, 77 (23) , 6651-6666. https://doi.org/10.1158/0008-5472.CAN-17-0899
  74. Caroline L. Wilson, Derek A. Mann, Lee A. Borthwick. Epigenetic reprogramming in liver fibrosis and cancer. Advanced Drug Delivery Reviews 2017, 121 , 124-132. https://doi.org/10.1016/j.addr.2017.10.011
  75. Giulia Stazi, Clemens Zwergel, Antonello Mai, Sergio Valente. EZH2 inhibitors: a patent review (2014-2016). Expert Opinion on Therapeutic Patents 2017, 27 (7) , 797-813. https://doi.org/10.1080/13543776.2017.1316976
  76. Yiping Wen, Jing Cai, Yaya Hou, Zaiju Huang, Zehua Wang. Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target. Oncotarget 2017, 8 (23) , 37974-37990. https://doi.org/10.18632/oncotarget.16467
  77. Ke-Sin Yan, Chia-Yuan Lin, Tan-Wei Liao, Cheng-Ming Peng, Shou-Chun Lee, Yi-Jui Liu, Wing Chan, Ruey-Hwang Chou. EZH2 in Cancer Progression and Potential Application in Cancer Therapy: A Friend or Foe?. International Journal of Molecular Sciences 2017, 18 (6) , 1172. https://doi.org/10.3390/ijms18061172
  78. Regan Stephenson, Ankur Singh. Drug discovery and therapeutic delivery for the treatment of B and T cell tumors. Advanced Drug Delivery Reviews 2017, 114 , 285-300. https://doi.org/10.1016/j.addr.2017.06.010
  79. Michael L. Curtin, Marina A. Pliushchev, Huan-Qiu Li, Maricel Torrent, Justin D. Dietrich, Clarissa G. Jakob, Haizhong Zhu, Hongyu Zhao, Ying Wang, Zhiqin Ji, Richard F. Clark, Kathy A. Sarris, Sujatha Selvaraju, Bailin Shaw, Mikkel A. Algire, Yupeng He, Paul L. Richardson, Ramzi F. Sweis, Chaohong Sun, Gary G. Chiang, Michael R. Michaelides. SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding. Bioorganic & Medicinal Chemistry Letters 2017, 27 (7) , 1576-1583. https://doi.org/10.1016/j.bmcl.2017.02.030
  80. Wei Qi, Kehao Zhao, Justin Gu, Ying Huang, Youzhen Wang, Hailong Zhang, Man Zhang, Jeff Zhang, Zhengtian Yu, Ling Li, Lin Teng, Shannon Chuai, Chao Zhang, Mengxi Zhao, HoMan Chan, Zijun Chen, Douglas Fang, Qi Fei, Leying Feng, Lijian Feng, Yuan Gao, Hui Ge, Xinjian Ge, Guobin Li, Andreas Lingel, Ying Lin, Yueqin Liu, Fangjun Luo, Minlong Shi, Long Wang, Zhaofu Wang, Yanyan Yu, Jue Zeng, Chenhui Zeng, Lijun Zhang, Qiong Zhang, Shaolian Zhou, Counde Oyang, Peter Atadja, En Li. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nature Chemical Biology 2017, 13 (4) , 381-388. https://doi.org/10.1038/nchembio.2304
  81. Raushan T. Kurmasheva, Melissa Sammons, Edward Favours, Jianwrong Wu, Dias Kurmashev, Katherine Cosmopoulos, Heike Keilhack, Christine R. Klaus, Peter J. Houghton, Malcolm A. Smith. Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatric Blood & Cancer 2017, 64 (3) https://doi.org/10.1002/pbc.26218
  82. Ling Li, Hailong Zhang, Man Zhang, Mengxi Zhao, Lijian Feng, Xiao Luo, Zhenting Gao, Ying Huang, Ophelia Ardayfio, Ji-Hu Zhang, Ying Lin, Hong Fan, Yuan Mi, Guobin Li, Lei Liu, Leying Feng, Fangjun Luo, Lin Teng, Wei Qi, Johannes Ottl, Andreas Lingel, Dirksen E. Bussiere, Zhengtian Yu, Peter Atadja, Chris Lu, En Li, Justin Gu, Kehao Zhao, . Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED. PLOS ONE 2017, 12 (1) , e0169855. https://doi.org/10.1371/journal.pone.0169855
  83. Virginia E. Duncan, Zheng Ping, Sooryanarayana Varambally, Deniz Peker. Loss of RUNX3 expression is an independent adverse prognostic factor in diffuse large B-cell lymphoma. Leukemia & Lymphoma 2017, 58 (1) , 179-184. https://doi.org/10.1080/10428194.2016.1180686
  84. Marjorie G. Zauderer. Standard Chemotherapy Options and Clinical Trials of Novel Agents for Mesothelioma. 2017, 313-345. https://doi.org/10.1007/978-3-319-53560-9_15
  85. Faisal Saeed Khan, Ijaz Ali, Ume Kalsoom Afridi, Muhammad Ishtiaq, Rashid Mehmood. Epigenetic mechanisms regulating the development of hepatocellular carcinoma and their promise for therapeutics. Hepatology International 2017, 11 (1) , 45-53. https://doi.org/10.1007/s12072-016-9743-4
  86. D. Harvey, M. Foley. Inhibitors of Epigenetic Regulation in Cancer. 2017, 281-307. https://doi.org/10.1016/B978-0-12-409547-2.12393-5
  87. Kenneth W. Duncan, John E. Campbell. Epigenetic Modulators. 2017, 227-227. https://doi.org/10.1007/7355_2017_30
  88. Anthos Christofides, Theodoros Karantanos, Kankana Bardhan, Vassiliki A. Boussiotis. Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2. Oncotarget 2016, 7 (51) , 85624-85640. https://doi.org/10.18632/oncotarget.12928
  89. Shuangping Guo, Qingxian Bai, Joseph Rohr, Yingmei Wang, Yang Liu, Kaixuan Zeng, Kangjie Yu, Xiumin Zhang, Zhe Wang. Clinicopathological features of primary diffuse large B‐cell lymphoma of the central nervous system – strong EZH2 expression implying diagnostic and therapeutic implication. APMIS 2016, 124 (12) , 1054-1062. https://doi.org/10.1111/apm.12623
  90. Anne Laugesen, Jonas Westergaard Højfeldt, Kristian Helin. Role of the Polycomb Repressive Complex 2 (PRC2) in Transcriptional Regulation and Cancer. Cold Spring Harbor Perspectives in Medicine 2016, 6 (9) , a026575. https://doi.org/10.1101/cshperspect.a026575
  91. Yunlong Wu, Junchi Hu, Hong Ding, Limin Chen, Yuanyuan Zhang, Rongfeng Liu, Pan Xu, Daohai Du, Wenchao Lu, Jingqiu Liu, Yan Liu, Yu-Chih Liu, Junyan Lu, Jin Zhang, Zhiyi Yao, Cheng Luo. Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays. Bioorganic & Medicinal Chemistry Letters 2016, 26 (15) , 3813-3817. https://doi.org/10.1016/j.bmcl.2016.05.018
  92. Matthieu Schapira, Cheryl H Arrowsmith. Methyltransferase inhibitors for modulation of the epigenome and beyond. Current Opinion in Chemical Biology 2016, 33 , 81-87. https://doi.org/10.1016/j.cbpa.2016.05.030
  93. Satoshi Kawano, Alexandra R. Grassian, Masumi Tsuda, Sarah K. Knutson, Natalie M. Warholic, Galina Kuznetsov, Shanqin Xu, Yonghong Xiao, Roy M. Pollock, Jesse S. Smith, Kevin K. Kuntz, Scott Ribich, Yukinori Minoshima, Junji Matsui, Robert A. Copeland, Shinya Tanaka, Heike Keilhack, . Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. PLOS ONE 2016, 11 (7) , e0158888. https://doi.org/10.1371/journal.pone.0158888
  94. Emi Takamatsu-Ichihara, Issay Kitabayashi. The roles of Polycomb group proteins in hematopoietic stem cells and hematological malignancies. International Journal of Hematology 2016, 103 (6) , 634-642. https://doi.org/10.1007/s12185-016-2011-5
  95. Lindsay M LaFave, Wendy Béguelin, Richard Koche, Matt Teater, Barbara Spitzer, Alan Chramiec, Efthymia Papalexi, Matthew D Keller, Todd Hricik, Katerina Konstantinoff, Jean-Baptiste Micol, Benjamin Durham, Sarah K Knutson, John E Campbell, Gil Blum, Xinxu Shi, Emma H Doud, Andrei V Krivtsov, Young Rock Chung, Inna Khodos, Elisa de Stanchina, Ouathek Ouerfelli, Prasad S Adusumilli, Paul M Thomas, Neil L Kelleher, Minkui Luo, Heike Keilhack, Omar Abdel-Wahab, Ari Melnick, Scott A Armstrong, Ross L Levine. Reply to "Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status". Nature Medicine 2016, 22 (6) , 578-579. https://doi.org/10.1038/nm.4094
  96. Prasoon Agarwal, Mohammad Alzrigat, Alba Atienza Párraga, Stefan Enroth, Umashankar Singh, Johanna Ungerstedt, Anders Österborg, Peter J. Brown, Anqi Ma, Jian Jin, Kenneth Nilsson, Fredrik Öberg, Antonia Kalushkova, Helena Jernberg-Wiklund. Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target. Oncotarget 2016, 7 (6) , 6809-6823. https://doi.org/10.18632/oncotarget.6843
  97. John R. Horton, Amanda Engstrom, Elizabeth L. Zoeller, Xu Liu, John R. Shanks, Xing Zhang, Margaret A. Johns, Paula M. Vertino, Haian Fu, Xiaodong Cheng. Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases. Journal of Biological Chemistry 2016, 291 (6) , 2631-2646. https://doi.org/10.1074/jbc.M115.698449
  98. Michel Wassef, Veronica Rodilla, Aurélie Teissandier, Bruno Zeitouni, Nadege Gruel, Benjamin Sadacca, Marie Irondelle, Margaux Charruel, Bertrand Ducos, Audrey Michaud, Matthieu Caron, Elisabetta Marangoni, Philippe Chavrier, Christophe Le Tourneau, Maud Kamal, Eric Pasmant, Michel Vidaud, Nicolas Servant, Fabien Reyal, Dider Meseure, Anne Vincent-Salomon, Silvia Fre, Raphaël Margueron. Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis. Genes & Development 2015, 29 (24) , 2547-2562. https://doi.org/10.1101/gad.269522.115
  99. Sheng F. Cai, Chun-Wei Chen, Scott A. Armstrong. Drugging Chromatin in Cancer: Recent Advances and Novel Approaches. Molecular Cell 2015, 60 (4) , 561-570. https://doi.org/10.1016/j.molcel.2015.10.042
  100. Lindsay M LaFave, Wendy Béguelin, Richard Koche, Matt Teater, Barbara Spitzer, Alan Chramiec, Efthymia Papalexi, Matthew D Keller, Todd Hricik, Katerina Konstantinoff, Jean-Baptiste Micol, Benjamin Durham, Sarah K Knutson, John E Campbell, Gil Blum, Xinxu Shi, Emma H Doud, Andrei V Krivtsov, Young Rock Chung, Inna Khodos, Elisa de Stanchina, Ouathek Ouerfelli, Prasad S Adusumilli, Paul M Thomas, Neil L Kelleher, Minkui Luo, Heike Keilhack, Omar Abdel-Wahab, Ari Melnick, Scott A Armstrong, Ross L Levine. Loss of BAP1 function leads to EZH2-dependent transformation. Nature Medicine 2015, 21 (11) , 1344-1349. https://doi.org/10.1038/nm.3947
Load all citations
  • Abstract

    Figure 1

    Figure 1. Representative reported EZH2 inhibitors.

    Figure 2

    Figure 2. SAR affords a potent, stable EZH2 inhibitor.

    Figure 3

    Figure 3. Effect of EPZ011989 concentration on the proliferation of WSU-DLCL2 cells in culture over an 11-day period.

    Figure 4

    Figure 4. Single dose PK in SCID mice following oral administration of 125, 250, 500, and 1000 mg/kg dosed as suspensions in 0.5% w/v methyl cellulose and 0.1% Tween-80 acidified with 1 mol equiv of HCl. LCC predicted efficacious plasma level for compound EPZ011989 (158 ng/mL) is shown by a horizontal, dashed line.

    Figure 5

    Figure 5. (a) Pharmacokinetic analysis of day 7 plasma samples for EPZ011989. (b) Pharmacodynamic analysis of histone methyl mark in bone marrow tissue at day 7 of dosing EPZ011989.

    Figure 6

    Figure 6. PK after oral dosing of EPZ011989 DTAL at doses of 30, 100, and 300 mg/kg.

    Figure 7

    Figure 7. Robust tumor growth inhibition seen at 250 and 500 mg/kg BID EPZ011989.

    Figure 8

    Figure 8. Methyl mark reduction observed in tumor tissue over time on day 7 of EPZ011989 administration.

    Figure 9

    Figure 9. Total and free plasma exposure time courses for EPZ011989 in the KARPAS-422 xenograft study. Values measured postdose on day 7 of 21.

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 16 other publications.

    1. 1
      Kuzmichev, A.; Nishioka, K.; Erdjument-Bromage, H.; Tempst, P.; Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein Genes Dev. 2002, 16, 2893 2905
    2. 2
      Cao, R.; Wang, L.; Xia, L.; Erdjument-Bromage, H.; Tempst, P.; Jones, R. S.; Zhang, Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing Science 2002, 298, 1039 1043
    3. 3
      Simon, J. A.; Lange, C. A. Roles of the EZH2 Histone Methyltransferase in Cancer Epigenetics Mutat. Res. 2008, 647, 21 29
    4. 4
      Knutson, S. K.; Warholic, N. M.; Wigle, T. J.; Klaus, C. R.; Allain, C. J.; Raimondi, A.; Porter-Scott, M.; Chesworth, R.; Moyer, M. P.; Copeland, R. A.; Richon, V. M.; Pollock, R. M.; Kuntz, K. W.; Keilhack, H. Durable Tumor Regression in Genetically Altered Malignant Rhabdoid Tumors by Inhibition of Methyltransferase EZH2 Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 7922 7927
    5. 5
      Sneeringer, C. J.; Porter-Scott, M.; Kuntz, K. W.; Knutson, S. K.; Pollock, R. M.; Richon, V. R.; Copeland, R. A. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (HEK27) in human B cell Lymphomas Proc. Natl. Acad. Sci. U.S.A. 2011, 107, 20980 20985
    6. 6
      Knutson, S. K.; Warholic, N. M.; Johnston, L. D.; Klaus, C. R.; Wigle, T. J.; Iwanowicz, D.; Littlefield, B. A.; Porter-Scott, M.; Smith, J.; Moyer, M. P.; Copeland, R. A.; Pollock, R. M.; Kuntz, K. W.; Raimondi, A.; Keilhack, H. Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocoericoid Receptor Agonists in Models of Germinal Center Non-Hodgekin Lymphomas PLoS One 2014, 9, e111840
    7. 7
      Ntziachristos, P.; Tsirigos, A.; Van Vlierberghe, P.; Nedjic, J.; Trimarchi, T.; Sol Flaherty, M.; Ferres-Marco, D.; da Ros, V.; Tang, Z.; Siegle, J.; Asp, P.; Hadler, M.; Rigo, I.; De Keersmaecker, K.; Patel, J.; Huynh, T.; Utro, F.; Poglio, S.; Samon, J. B.; Paietta, E.; Recevskis, J.; Rowe, J. M.; Rabadan, R.; Levine, R. L.; Brown, S.; Pflumio, F.; Dominguez, M.; Ferrando, A.; Aifantis, I. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia Nat. Med. 2012, 18, 298 303
    8. 8
      Wang, S.; Robertson, G. P.; Zhu, J. A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers Gene 2004, 343, 69 78
    9. 9
      Knutson, S. K.; Wigle, T. J.; Warholic, N. M.; Sneeringer, C. J.; Allain, C. J.; Klaus, C. R.; Sacks, J. D.; Raimondi, A.; Majer, C. R.; Song, J.; Porter-Scott, M.; Jin, L.; Smith, J. J.; Olhava, E. J.; Chesworth, R.; Moyer, M.; Richon, V. M.; Copeland, R. A.; Keilhack, H.; Pollock, R. M.; Kuntz, K. W. A Selective Inhibitor of EZH2 blocks H3K27 methylation and Kills Mutant Lymphoma Cells Nat. Chem. Biol. 2012, 8, 890 896
    10. 10
      Konze, K. D.; Ma, A.; Li, F.; Barsyte-Lovejoy, D.; Parton, T.; MacNevin, C. J.; Liu, F.; Gao, C.; Huang, X.-P.; Kuznetsova, E.; Rougie, M.; Jiang, A.; Patterden, S. G.; Norris, J. L.; James, L. I.; Roth, B. L.; Brown, P. J.; Frye, S. V.; Arrowsmith, C. H.; Hahn, K. M.; Wang, G. G.; Vedadi, M.; Jin, J. An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1 ACS Chem. Biol. 2013, 8, 1324 1334
    11. 11
      Verma, S. K.; Tian, X.; LaFrance, L. V.; Duquenne, C.; Suarez, D. P.; Newlander, K. A.; Romeril, S. P.; Burgess, J. L.; Grant, S. W.; Brackley, J. A.; Graves, A. P.; Scherzer, D. A.; Shu, A.; Thompson, C.; Ott, H. M.; Van Aller, G. S.; Machutta, C. A.; Diaz, E.; Jiang, Y.; Johnson, N. W.; Knight, S. D.; Kruger, R. G.; McCabe, M. T.; Dhanak, D.; Tummino, P. J.; Creasy, C. L.; Miller, W. H. Identification of Potent, Selective Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2 ACS Med. Chem. Lett. 2012, 3, 1091 1096
    12. 12
      Qi, W.; Chan, H.; Teng, L.; Li, L.; Chuai, S.; Zhang, R.; Zeng, J.; Li, M.; Fan, H.; Lin, Y.; Gu, J.; Ardayfio, O.; Zhang, J.-H.; Yan, X.; Fang, J.; Mi, Y.; Zhang, M.; Zhao, T.; Feng, G.; Chen, Z.; Li, G.; Ynag, T.; Zhao, K.; Liu, X.; Yu, Z.; Lu, C. X.; Atadja, P.; Li, E. Selective inhibition of EZH2 by a small molecule inhibitor blocks tumor cell proliferation Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 21360 21365
    13. 13
      Bradley, W. D.; Arora, S.; Busby, J.; Balasubramanian, S.; Gehling, V.; Nasveschuk, C. G.; Vaswani, R. G.; Yuan, C.-C.; Hatton, C.; Zhao, F.; Williamson, K. E.; Iyer, P.; Méndez, J.; Campbell, R.; Cantone, N.; Garapaty-Rao, S.; Audia, J.; Cook, A. S.; Dakin, L. A.; Albrecht, B. K.; Harmange, J.-C.; Daniels, D. L.; Cummings, R. T.; Bryant, B. M.; Normant, E.; Trojer, P. EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation Chem. Biol. 2014, 21, 1463 1475
    14. 14
      Garapaty-Rao, S.; Nasvechuk, C.; Gagnon, A.; Chan, E. Y.; Sandy, P.; Busby, J.; Balasubramanian, S.; Campbell, R.; Zhao, F.; Bergeron, L.; Audia, J. E.; Albrecht, B. K.; Harmange, J.-C.; Cummings, R.; Trojer, P. Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth Chem. Biol. 2013, 20, 1329 1339
    15. 15
      Nasveschuk, C. G.; Gagnon, A.; Garapaty-Rao, S.; Balasubramanian, S.; Campbell, R.; Lee, C.; Zhao, F.; Bergeron, L.; Cummings, R.; Trojer, P.; Audia, J. E.; Albrecht, B. K.; Harmange, J.-C. P. Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2 ACS Med. Chem. Lett. 2014, 5, 378 383
    16. 16
      As calculated using ChemAxon JChem for Excel software. http://www.chemaxon.com/conf/Calculating_pKa_values_of_small_and_large_molecules.pdf.
  • Supporting Information

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    Detailed biological assay information, and procedures and characterization data for the synthesis of EPZ011989. This material is available free of charge via the Internet at http://pubs.acs.org.


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect