title: Identification of potent, selective KDM5 inhibitors.
abstract: This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization.
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States. Electronic address: victor.gehling@constellationpharma.com.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Gehling
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: LeBlanc
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Florence
authors.initials: F
authors.lastname: Poy
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Shobu
authors.initials: S
authors.lastname: Odate
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Shane
authors.initials: S
authors.lastname: Buker
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Arora
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Kaylyn E
authors.initials: KE
authors.lastname: Williamson
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Sandy
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bailey
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Louise
authors.initials: L
authors.lastname: Bergeron
authors.affiliation: WuXi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Mao
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Erica
authors.initials: E
authors.lastname: VanderPorten
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
authors.affiliation: Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
mesh_terms: D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D051381:Rats; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2
keywords: Epigenetics; Histone lysine demethylase; JARID1; KDM5