title: Development of methyl isoxazoleazepines as inhibitors of BET.
abstract: In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA. Electronic address: mike.hewitt@constellationpharma.com.
authors: Michael C
authors: MC
authors: Hewitt
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Yves
authors: Y
authors: Leblanc
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Victor S
authors: VS
authors: Gehling
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Rishi G
authors: RG
authors: Vaswani
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Alexandre
authors: A
authors: Côté
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Christopher G
authors: CG
authors: Nasveschuk
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Alexander M
authors: AM
authors: Taylor
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Jean-Christophe
authors: JC
authors: Harmange
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: James E
authors: JE
authors: Audia
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Eneida
authors: E
authors: Pardo
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Rich
authors: R
authors: Cummings
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Shivangi
authors: S
authors: Joshi
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Peter
authors: P
authors: Sandy
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Jennifer A
authors: JA
authors: Mertz
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Robert J
authors: RJ
authors: Sims
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Louise
authors: L
authors: Bergeron
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Barbara M
authors: BM
authors: Bryant
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Steve
authors: S
authors: Bellon
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Florence
authors: F
authors: Poy
authors: Hariharan
authors: H
authors: Jayaram
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Hariharan
authors: H
authors: Jayaran
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Yong
authors: Y
authors: Tang
authors: Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
authors: Brian K
authors: BK
authors: Albrecht
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010080:Oxazoles; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C109570:BRDT protein, human; C000604976:methyl isoxazoleazepine
keywords: BET inhibitors; Bromodomains; Isoxazoles; MYC; Unbound clearance