title: Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.
abstract: In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
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: Alexandre
authors.initials: A
authors.lastname: Côté
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: Christopher G
authors.initials: CG
authors.lastname: Nasveschuk
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: Louise
authors.initials: L
authors.lastname: Bergeron
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Nico
authors.initials: N
authors.lastname: Cantone
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Cooper
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
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: 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: Jennifer A
authors.initials: JA
authors.lastname: Mertz
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Adrianne
authors.initials: A
authors.lastname: Neiss
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Meara
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: Florence
authors.initials: F
authors.lastname: Poy
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: Jeffrey
authors.initials: J
authors.lastname: Supko
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: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
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: James E
authors.initials: JE
authors.lastname: Audia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001381:Azepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051381:Rats; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins