title: Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.
abstract: Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Srimoyee
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Taylor
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chin
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Hon-Ren
authors.initials: HR
authors.lastname: Huang
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Conery
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Mertz
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Andres
authors.initials: A
authors.lastname: Salmeron
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Pranal J
authors.initials: PJ
authors.lastname: Dakle
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Deanna
authors.initials: D
authors.lastname: Mele
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cote
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Hari
authors.initials: H
authors.lastname: Jayaram
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Setser
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Florence
authors.initials: F
authors.lastname: Poy
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Denise
authors.initials: D
authors.lastname: DeAlmeida-Nagata
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Peter
authors.initials: P
authors.lastname: Sandy
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Charlie
authors.initials: C
authors.lastname: Hatton
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Romero
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Eugene
authors.initials: E
authors.lastname: Chiang
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Thornik
authors.initials: T
authors.lastname: Reimer
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Terry
authors.initials: T
authors.lastname: Crawford
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Eneida
authors.initials: E
authors.lastname: Pardo
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Venita G
authors.initials: VG
authors.lastname: Watson
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Laura
authors.initials: L
authors.lastname: Zawadzke
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bryant
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Magnuson
authors.affiliation: Genentech, Inc., South San Francisco, California 94080.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Grogan
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Steve F
authors.initials: SF
authors.lastname: Bellon
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and robert.sims@constellationpharma.com.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sims
authors.affiliation: From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and jose.lora@constellationpharma.com.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lora
mesh_terms: D000107:Acetylation / Q000187:drug effects; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006657:Histones; D054852:Small Molecule Libraries; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: Treg, CBP, EP300, bromodomain, histone; acetylation; cellular immune response; chemical biology; chromatin regulation; forkhead box P3 (FOXP3)