title: Discovery, design, and synthesis of indole-based EZH2 inhibitors.
abstract: The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 μM), cellular potency (EC50=0.080 μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA. Electronic address: victor.gehling@constellationpharma.com.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Gehling
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Rishi G
authors.initials: RG
authors.lastname: Vaswani
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Nasveschuk
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Iyer
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Srividya
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lee
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cook
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gagnon
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Cambridge, MA 02142, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D000071221:Enhancer of Zeste Homolog 2 Protein; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D054852:Small Molecule Libraries; C030374:indole; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: EZH2; Epigenetics; Histone methyltransferase; PRC2; Pyridone