title: Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains.
abstract: The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.
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: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
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: Shumei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Côté
authors.affiliation: Constellation Pharmaceuticals, Inc. 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: Maureen H
authors.initials: MH
authors.lastname: Beresini
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Burdick
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Cummings
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hewitt
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Hon-Ren
authors.initials: HR
authors.lastname: Huang
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Jayaram
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: Ying
authors.initials: Y
authors.lastname: Jiang
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: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Nasveschuk
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Eneida
authors.initials: E
authors.lastname: Pardo
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Florence
authors.initials: F
authors.lastname: Poy
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: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
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: Zhaowu
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Laura E
authors.initials: LE
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: Xiaoyu
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Magnuson
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Bellon
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018797:Cell Cycle Proteins; D004305:Dose-Response Relationship, Drug; D031541:Fluorescence Resonance Energy Transfer; D005470:Fluorometry; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D035381:TATA-Binding Protein Associated Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D035362:Transcription Factor TFIID / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014867:Water / Q000737:chemistry*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D008024:Ligands; D009687:Nuclear Proteins; D011728:Pyridones; D011758:Pyrroles; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; D014867:Water; C000619634:6-methyl pyrrolopyridone; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C587454:BRD9 protein, human; C576521:Cecr2 protein, human; C486221:TAF2 protein, human; C069001:TATA-binding protein associated factor 250 kDa