title: Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637).
abstract: CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.
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: Alexandre
authors.initials: A
authors.lastname: Côté
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: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Pastor
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: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Romero
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Crawford
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: Hariharan
authors.initials: H
authors.lastname: Jayaram
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Setser
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Maureen H
authors.initials: MH
authors.lastname: Beresini
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Gladys
authors.initials: G
authors.lastname: de Leon Boenig
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Conery
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: Leslie A
authors.initials: LA
authors.lastname: Dakin
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: E Megan
authors.initials: EM
authors.lastname: Flynn
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Huang
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Kaufman
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keller
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Tommy
authors.initials: T
authors.lastname: Lai
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Jiangpeng
authors.initials: J
authors.lastname: Liao
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Liu
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Henry
authors.initials: H
authors.lastname: Lu
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: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Yongyun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Zhaowu
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Fen
authors.initials: F
authors.lastname: Yan
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.affiliation: Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Zawadzke
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Wuxi AppTec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhu
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: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
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: James E
authors.initials: JE
authors.lastname: Audia
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
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: Bromodomain; CBP; CREBBP; EP300; benzodiazepinone