title: Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.
abstract: The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Gehling
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hewitt
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Rishi G
authors.initials: RG
authors.lastname: Vaswani
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: Leblanc
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Côté
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Nasveschuk
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Eneida
authors.initials: E
authors.lastname: Pardo
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Shivangi
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Sandy
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Mertz
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sims
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Louise
authors.initials: L
authors.lastname: Bergeron
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bryant
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Bellon
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Florence
authors.initials: F
authors.lastname: Poy
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Jayaram
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwantpur, Bangalore 560 022, India.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Sankaranarayanan
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwantpur, Bangalore 560 022, India.
authors.forename: Sreegouri
authors.initials: S
authors.lastname: Yellapantula
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwantpur, Bangalore 560 022, India.
authors.forename: Nandana
authors.initials: N
authors.lastname: Bangalore Srinivasamurthy
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwantpur, Bangalore 560 022, India.
authors.forename: Swarnakumari
authors.initials: S
authors.lastname: Birudukota
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
keywords: BET inhibitors; MYC; bromodomain; fragments; isoxazoles