title: 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.
abstract: Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50= 0.002 μM, cellular EC50= 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Rishi G
authors.initials: RG
authors.lastname: Vaswani
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Gehling
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cook
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Nasveschuk
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Iyer
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Srividya
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Lee
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Nico
authors.initials: N
authors.lastname: Cantone
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Justin
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Wilson
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gamblin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D010880:Piperidines; C000619999:(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; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase