title: Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.
abstract: Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid rhabdoid tumors. This alteration is hypothesized to confer oncogenic dependency on EZH2 in these cancers. We report the discovery of a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity, (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide). The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells. Treatment of xenograft-bearing mice with (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide) leads to dose-dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers.
authors.affiliation: Epizyme, Inc, Cambridge, MA 02139, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Warholic
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.forename: Christine R
authors.initials: CR
authors.lastname: Klaus
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Allain
authors.forename: Alejandra
authors.initials: A
authors.lastname: Raimondi
authors.forename: Margaret
authors.initials: M
authors.lastname: Porter Scott
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015195:Drug Design; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D018335:Rhabdoid Tumor / Q000201:enzymology* / Q000235:genetics*
chemical_list: C582255:(N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl9tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-91,1'-biphenyl0-3-carboxamide; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D006657:Histones; D011725:Pyridines; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: EZH2 inhibitor; epigenetic cancer therapy