title: Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth.
abstract: The histone methyltransferase enhancer of Zeste homolog 2 (EZH2) is a candidate oncogene due to its prevalent overexpression in malignant diseases, including late stage prostate and breast cancers. The dependency of cancer cells on EZH2 activity is also predicated by recurrent missense mutations residing in the catalytic domain of EZH2 that have been identified in subtypes of diffuse large B cell lymphoma, follicular lymphoma and melanoma. Herein, we report the identification of a highly selective small molecule inhibitor series of EZH2 and EZH1. These compounds inhibit wild-type and mutant versions of EZH2 with nanomolar potency, suppress global histone H3-lysine 27 methylation, affect gene expression, and cause selective proliferation defects. These compounds represent a structurally distinct EZH2 inhibitor chemotype for the exploration of the role of Polycomb Repressive Complex 2-mediated H3K27 methylation in various biological contexts.
authors.affiliation: Department of Biology, Constellation Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Garapaty-Rao
authors.forename: Christopher
authors.initials: C
authors.lastname: Nasveschuk
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gagnon
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chan
authors.forename: Peter
authors.initials: P
authors.lastname: Sandy
authors.forename: Jennifer
authors.initials: J
authors.lastname: Busby
authors.forename: Srividya
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Louise
authors.initials: L
authors.lastname: Bergeron
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: Richard
authors.initials: R
authors.lastname: Cummings
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D006367:HeLa Cells; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D015394:Molecular Structure; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; C103523:EZH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2