title: Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.
abstract: Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.
authors: Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.|WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors: Natalie H
authors: NH
authors: Theodoulou
authors: Computational & Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Paul
authors: P
authors: Bamborough
authors: Department of Pathology, Gurdon Institute , Tennis Court Road, Cambridge CB2 1QN, U.K.
authors: Andrew J
authors: AJ
authors: Bannister
authors: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Isabelle
authors: I
authors: Becher
authors: Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Rino A
authors: RA
authors: Bit
authors: Department of Pathology, Gurdon Institute , Tennis Court Road, Cambridge CB2 1QN, U.K.
authors: Ka Hing
authors: KH
authors: Che
authors: Computational & Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Chun-wa
authors: CW
authors: Chung
authors: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Antje
authors: A
authors: Dittmann
authors: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Gerard
authors: G
authors: Drewes
authors: Department of Chemical Biology, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors: David H
authors: DH
authors: Drewry
authors: Biological Sciences, Molecular Discovery Research, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Laurie
authors: L
authors: Gordon
authors: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Paola
authors: P
authors: Grandi
authors: Biological Sciences, Molecular Discovery Research, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Melanie
authors: M
authors: Leveridge
authors: Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Matthew
authors: M
authors: Lindon
authors: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Anne-Marie
authors: AM
authors: Michon
authors: Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Judit
authors: J
authors: Molnar
authors: Department of Pathology, Gurdon Institute , Tennis Court Road, Cambridge CB2 1QN, U.K.
authors: Samuel C
authors: SC
authors: Robson
authors: WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors: Nicholas C O
authors: NC
authors: Tomkinson
authors: Department of Pathology, Gurdon Institute , Tennis Court Road, Cambridge CB2 1QN, U.K.
authors: Tony
authors: T
authors: Kouzarides
authors: Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Rab K
authors: RK
authors: Prinjha
authors: Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
authors: Philip G
authors: PG
authors: Humphreys
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D054852:Small Molecule Libraries; D014157:Transcription Factors; C587454:BRD9 protein, human; D000092468:Bromodomain Containing Proteins