Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase

Journal of Medicinal Chemistry

Volumn 60, Issue 1, 2017, Pages 415-427

  Lingel, Andreas ^a,c   Sendzik, Martin ^a   Huang, Ying ^b   Shultz, Michael D ^b   Cantwell, John ^a   Dillon, Michael P ^a,d   Fu, Xingnian ^b   Fuller, John ^a   Gabriel, Tobias ^b,c   Gu, Justin ^b   Jiang, Xiangqing ^b   Li, Ling ^b   Liang, Fang ^b   McKenna, Maureen ^a   Qi, Wei ^b   Rao, Weijun ^b   Sheng, Xijun ^b   Shu, Wei ^a   Sutton, James ^a,d   Taft, Benjamin ^a   Wang, Long ^b   Zeng, Jue ^b   Zhang, Hailong ^b,e   Zhang, Maya ^b   Zhao, Kehao ^b   Lindvall, Mika ^a   Bussiere, Dirksen E ^a   more..

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^b Novartis Institutes for Biomedical Research   (China)

^c NOVARTIS PHARMA AG   (Switzerland)

^d IDEAYA Biosciences Inc   (United States)

^e ARRAY BIOPHARMA INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(BENZO[D][1,3]DIOXOL 4 YLMETHYL) 1 ISOPROPYL 5,6,7,8 TETRAHYDROIMIDAZO[1,5 A]PYRIDIN 3 AMINE; 3 (3 METHOXYBENZYL)PIPERIDINE; 3 (3 METHOXYBENZYL)PIPERIDINE 1 CARBOXIMIDAMIDE; 3 (4 FLUORO 3 METHOXYBENZYL)PIPERIDINE; 3 (BENZOFURAN 4 YLMETHYL)PIPERIDINE; 3 (BENZOFURAN 4 YLMETHYL)PIPERIDINE 1 CARBOXAMIDE; 3 (BENZOFURAN 4 YLMETHYL)PIPERIDINE 1 CARBOXIMIDAMIDE TRIFLATE; 3 (BENZOFURAN 7 YLMETHYL)PIPERIDINE; 3 (BENZOFURAN 7 YLMETHYL)PIPERIDINE 1 CARBOXIMIDAMIDE TRIFLATE; 3 (BENZO[D][1,3]DIOXOL 4 YLMETHYL)PIPERIDINE; 3 (BENZO[D][1,3]DIOXOL 5 YLMETHYL)PIPERIDINE 1 CARBOXIMIDAMIDE; 6 (2 FLUORO 5 METHOXYBENZYL) 1 ISOPROPYL 5,6,7,8 TETRAHYDROIMIDAZO[1,5 A]PYRIDIN 3 AMINE; 6 (2 FLUOROBENZYL) 1 ISOPROPYL 5,6,7,8 TETRAHYDROIMIDAZO[1,5 A]PYRIDIN 3 AMINE; 6 (BENZOFURAN 4 YLMETHYL) 5,6,7,8 TETRAHYDROIMIDAZO[1,5 A]PYRIDIN 3 AMINE; 6 (BENZO[D][1,3]DIOXOL 4 YLMETHYL) 5,6,7,8 TETRAHYDROIMIDAZO [1,5 A]PYRIDIN 3 AMINE; METHYLTRANSFERASE INHIBITOR; POLYCOMB REPRESSIVE COMPLEX 2; UNCLASSIFIED DRUG; ENZYME INHIBITOR; METHYLTRANSFERASE;

ALLOSTERISM; ARTICLE; CACO-2 CELL LINE; CELL PROLIFERATION; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG MECHANISM; DRUG POTENCY; IC50; IN VITRO STUDY; PHARMACOPHORE; PROCESS OPTIMIZATION; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; GENETIC EPIGENESIS; HUMAN; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; PROTON NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ALLOSTERIC REGULATION; CACO-2 CELLS; CHROMATOGRAPHY, LIQUID; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; EPIGENESIS, GENETIC; HUMANS; INHIBITORY CONCENTRATION 50; MASS SPECTROMETRY; METHYLTRANSFERASES; MOLECULAR STRUCTURE; POLYCOMB REPRESSIVE COMPLEX 2; PROTON MAGNETIC RESONANCE SPECTROSCOPY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 85018193068     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b01473     Document Type: Article

References (35)

1. Margueron, R.; Reinberg, D. The Polycomb Complex PRC2 and Its Mark in Life Nature 2011, 469, 343-349 10.1038/nature09784
2. Cao, R.; Zhang, Y. SUZ12 Is Required for Both the Histone Methyltransferase Activity and the Silencing Function of the EED-EZH2 Complex Mol. Cell 2004, 15, 57-67 10.1016/j.molcel.2004.06.020
3. Ciferri, C.; Lander, G. C.; Maiolica, A.; Herzog, F.; Aebersold, R.; Nogales, E. Molecular Architecture of Human Polycomb Repressive Complex 2 eLife 2012, 1, e00005 10.7554/eLife.00005
4. Brooun, A.; Gajiwala, K. S.; Deng, Y.-L.; Liu, W.; Bolaños, B.; Bingham, P.; He, Y.-A.; Diehl, W.; Grable, N.; Kung, P.-P.; Sutton, S.; Maegley, K. A.; Yu, X.; Stewart, A. E. Polycomb Repressive Complex 2 Structure with Inhibitor Reveals a Mechanism of Activation and Drug Resistance Nat. Commun. 2016, 7, 11384 10.1038/ncomms11384
5. Jiao, L.; Liu, X. Structural Basis of Histone H3K27 Trimethylation by an Active Polycomb Repressive Complex 2 Science 2015, 350, aac4383-aac4383 10.1126/science.aac4383
6. Justin, N.; Zhang, Y.; Tarricone, C.; Martin, S. R.; Chen, S.; Underwood, E.; De Marco, V.; Haire, L. F.; Walker, P. a; Reinberg, D.; Wilson, J. R.; Gamblin, S. J. Structural Basis of Oncogenic Histone H3K27M Inhibition of Human Polycomb Repressive Complex 2 Nat. Commun. 2016, 7, 11316 10.1038/ncomms11316
7. McCabe, M. T.; Creasy, C. L. EZH2 as a Potential Target in Cancer Therapy Epigenomics 2014, 6, 341-351 10.2217/epi.14.23
8. Varambally, S.; Dhanasekaran, S. M.; Zhou, M.; Barrette, T. R.; Kumar-Sinha, C.; Sanda, M. G.; Ghosh, D.; Pienta, K. J.; Sewalt, R. G.; Otte, A. P.; Rubin, M. A.; Chinnaiyan, A. M. The Polycomb Group Protein EZH2 Is Involved in Progression of Prostate Cancer Nature 2002, 419, 624-629 10.1038/nature01075
9. Morin, R. D.; Johnson, N. A.; Severson, T. M.; Mungall, A. J.; An, J.; Goya, R.; Paul, J. E.; Boyle, M.; Woolcock, B. W.; Kuchenbauer, F.; Yap, D.; Humphries, R. K.; Griffith, O. L.; Shah, S.; Zhu, H.; Kimbara, M.; Shashkin, P.; Charlot, J. F.; Tcherpakov, M.; Corbett, R.; Tam, A.; Varhol, R.; Smailus, D.; Moksa, M.; Zhao, Y.; Delaney, A.; Qian, H.; Birol, I.; Schein, J.; Moore, R.; Holt, R.; Horsman, D. E.; Connors, J. M.; Jones, S.; Aparicio, S.; Hirst, M.; Gascoyne, R. D.; Marra, M. A. Somatic Mutations Altering EZH2 (Tyr641) in Follicular and Diffuse Large B-Cell Lymphomas of Germinal-Center Origin Nat. Genet. 2010, 42, 181-185 10.1038/ng.518
10. Takawa, M.; Masuda, K.; Kunizaki, M.; Daigo, Y.; Takagi, K.; Iwai, Y.; Cho, H.-S.; Toyokawa, G.; Yamane, Y.; Maejima, K.; Field, H. I.; Kobayashi, T.; Akasu, T.; Sugiyama, M.; Tsuchiya, E.; Atomi, Y.; Ponder, B. A. J.; Nakamura, Y.; Hamamoto, R. Validation of the Histone Methyltransferase EZH2 as a Therapeutic Target for Various Types of Human Cancer and as a Prognostic Marker Cancer Sci. 2011, 102, 1298-1305 10.1111/j.1349-7006.2011.01958.x
11. 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.; Scott, M. P.; Jin, L.; Smith, J. J.; Olhava, E. J.; Chesworth, R.; Moyer, M. P.; 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 10.1038/nchembio.1084
12. McCabe, M. T.; Ott, H. M.; Ganji, G.; Korenchuk, S.; Thompson, C.; Van Aller, G. S.; Liu, Y.; Graves, A. P.; Della Pietra, A., III; Diaz, E.; LaFrance, L. V.; Mellinger, M.; Duquenne, C.; Tian, X.; Kruger, R. G.; McHugh, C. F.; Brandt, M.; Miller, W. H.; Dhanak, D.; Verma, S. K.; Tummino, P. J.; Creasy, C. L. EZH2 Inhibition as a Therapeutic Strategy for Lymphoma with EZH2-Activating Mutations Nature 2012, 492, 108-112 10.1038/nature11606
13. Konze, K. D.; Ma, A.; Li, F.; Barsyte-Lovejoy, D.; Parton, T.; Macnevin, C. J.; Liu, F.; Gao, C.; Huang, X.; Kuznetsova, E.; Rougie, M.; Jiang, A.; Pattenden, 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 10.1021/cb400133j
14. 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 10.1021/ml3003346
15. 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.; Zhou, T.; Feng, G.; Chen, Z.; Li, G.; Yang, 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 Cells Proliferation Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 21360-21365 10.1073/pnas.1210371110
16. Garapaty-Rao, S.; Nasveschuk, 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 10.1016/j.chembiol.2013.09.013
17. 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. P. Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2 ACS Med. Chem. Lett. 2014, 5, 378-383 10.1021/ml400494b
18. Gehling, V. S.; Vaswani, R. G.; Nasveschuk, C. G.; Duplessis, M.; Iyer, P.; Balasubramanian, S.; Zhao, F.; Good, A. C.; Campbell, R.; Lee, C.; Dakin, L. A.; Cook, A. S.; Gagnon, A.; Harmange, J.-C.; Audia, J. E.; Cummings, R. T.; Normant, E.; Trojer, P.; Albrecht, B. K. Discovery, Design, and Synthesis of Indole-Based EZH2 Inhibitors Bioorg. Med. Chem. Lett. 2015, 25, 3644-3649 10.1016/j.bmcl.2015.06.056
19. Kim, K. H.; Roberts, C. W. M. Targeting EZH2 in Cancer Nat. Med. 2016, 22, 128-134 10.1038/nm.4036
20. Kim, W.; Bird, G. H.; Neff, T.; Guo, G.; Kerenyi, M. A.; Walensky, L. D.; Orkin, S. H. Targeted Disruption of the EZH2-EED Complex Inhibits EZH2-Dependent Cancer Nat. Chem. Biol. 2013, 9, 643-650 10.1038/nchembio.1331
21. Han, Z.; Xing, X.; Hu, M.; Zhang, Y.; Liu, P.; Chai, J. Structural Basis of EZH2 Recognition by EED Structure 2007, 15, 1306-1315 10.1016/j.str.2007.08.007
22. Margueron, R.; Justin, N.; Ohno, K.; Sharpe, M. L.; Son, J.; Drury, W. J., III; Voigt, P.; Martin, S. R.; Taylor, W. R.; De Marco, V.; Pirrotta, V.; Reinberg, D.; Gamblin, S. J. Role of the Polycomb Protein EED in the Propagation of Repressive Histone Marks Nature 2009, 461, 762-767 10.1038/nature08398
23. Xu, C.; Bian, C.; Yang, W.; Galka, M.; Ouyang, H.; Chen, C.; Qiu, W.; Liu, H.; Jones, A. E.; MacKenzie, F.; Pan, P.; Li, S. S.-C.; Wang, H.; Min, J. Binding of Different Histone Marks Differentially Regulates the Activity and Specificity of Polycomb Repressive Complex 2 (PRC2) Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 19266-19271 10.1073/pnas.1008937107
24. Kozakov, D.; Hall, D. R.; Jehle, S.; Luo, L.; Ochiana, S. O.; Jones, E. V.; Pollastri, M.; Allen, K. N.; Whitty, A.; Vajda, S. Ligand Deconstruction: Why Some Fragment Binding Positions Are Conserved and Others Are Not Proc. Natl. Acad. Sci. U. S. A. 2015, 112, E2585-E2594 10.1073/pnas.1501567112
25. Chen, H.; Zhou, X.; Wang, A.; Zheng, Y.; Gao, Y.; Zhou, J. Evolutions in Fragment-Based Drug Design: The Deconstruction-Reconstruction Approach Drug Discovery Today 2015, 20, 105-113 10.1016/j.drudis.2014.09.015
26. Wilson, B. G.; Wang, X.; Shen, X.; McKenna, E. S.; Lemieux, M. E.; Cho, Y.-J.; Koellhoffer, E. C.; Pomeroy, S. L.; Orkin, S. H.; Roberts, C. W. M. Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic Transformation Cancer Cell 2010, 18, 316-328 10.1016/j.ccr.2010.09.006
27. BioLoom Database; BioByte Corp.: 201 W. 4th St., #204, Claremont, CA 91711-4707; http://www.biobyte.com/bb/prod/bioloom.html.
28. Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition Science 2007, 317, 1881-1887 10.1126/science.1131943
29. Gibaja, V.; Shen, F.; Harari, J.; Korn, J.; Ruddy, D.; Saenz-Vash, V.; Zhai, H.; Rejtar, T.; Paris, C. G.; Yu, Z.; Lira, M.; King, D.; Qi, W.; Keen, N.; Hassan, A. Q.; Chan, H. M. Development of Secondary Mutations in Wild-Type and Mutant EZH2 Alleles Cooperates to Confer Resistance to EZH2 Inhibitors Oncogene 2016, 35, 558-566 10.1038/onc.2015.114
30. Baker, T.; Nerle, S.; Pritchard, J.; Zhao, B.; Rivera, V. M.; Garner, A.; Gonzalvez, F. Acquisition of a Single EZH2 D1 Domain Mutation Confers Acquired Resistance to EZH2-Targeted Inhibitors Oncotarget 2015, 6, 32646-32655 10.18632/oncotarget.5066
31. Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and Development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501 10.1107/S0907444910007493
32. Bricogne, G.; Blanc, E.; Brandl, M.; Flensburg, C.; Keller, P.; Paciorek, W.; Roversi, P.; Sharff, A.; Smart, O. S.; Vonrhein, C.; Womack, T. O. BUSTER, version 2.11.6; Global Phasing Ltd.: Cambridge, United Kingdom, 2016.
33. Adams, P. D.; Afonine, P. V.; Bunkóczi, G.; Chen, V. B.; Davis, I. W.; Echols, N.; Headd, J. J.; Hung, L.-W.; Kapral, G. J.; Grosse-Kunstleve, R. W.; McCoy, A. J.; Moriarty, N. W.; Oeffner, R.; Read, R. J.; Richardson, D. C.; Richardson, J. S.; Terwilliger, T. C.; Zwart, P. H. PHENIX: A Comprehensive Python-Based System for Macromolecular Structure Solution Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 213-221 10.1107/S0907444909052925
34. Li, S.; Gu, X. J.; Hao, Q.; Fan, H.; Li, L.; Zhou, S.; Zhao, K.; Chan, H. M.; Wang, Y. K. A Liquid Chromatography/mass Spectrometry-Based Generic Detection Method for Biochemical Assay and Hit Discovery of Histone Methyltransferases Anal. Biochem. 2013, 443, 214-221 10.1016/j.ab.2013.08.029
35. Gedeck, P.; Lu, Y.; Skolnik, S.; Rodde, S.; Dollinger, G.; Jia, W.; Berellini, G.; Vianello, R.; Faller, B.; Lombardo, F. Benefit of Retraining pKa Models Studied Using Internally Measured Data J. Chem. Inf. Model. 2015, 55, 1449-1459 10.1021/acs.jcim.5b00172