2. Academic Validation
  3. Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition

Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition

  • J Med Chem. 2016 Feb 25;59(4):1425-39. doi: 10.1021/acs.jmedchem.5b00256.
Natalie H Theodoulou 1 2,  Paul Bamborough 3,  Andrew J Bannister 4,  Isabelle Becher 5,  Rino A Bit 1,  Ka Hing Che 4,  Chun-wa Chung 3,  Antje Dittmann 5,  Gerard Drewes 5,  David H Drewry 6,  Laurie Gordon 7,  Paola Grandi 5,  Melanie Leveridge 7,  Matthew Lindon 1,  Anne-Marie Michon 5,  Judit Molnar 1,  Samuel C Robson 4,  Nicholas C O Tomkinson 2,  Tony Kouzarides 4,  Rab K Prinjha 1,  Philip G Humphreys 1
Affiliations

Affiliations

  • 1 Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
  • 2 WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • 3 Computational & Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
  • 4 Department of Pathology, Gurdon Institute , Tennis Court Road, Cambridge CB2 1QN, U.K.
  • 5 Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline R&D , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • 6 Department of Chemical Biology, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
  • 7 Biological Sciences, Molecular Discovery Research, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.
PMID: 25856009 DOI: 10.1021/acs.jmedchem.5b00256
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.

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