Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe

  • J Med Chem. 2023 Nov 15. doi: 10.1021/acs.jmedchem.3c00906.
Erin Bradley  1  2 ,  Lucia Fusani  1  2 ,  Chun-Wa Chung  1 ,  Peter D Craggs  1 ,  Emmanuel H Demont  1 ,  Philip G Humphreys  1 ,  Darren J Mitchell  1 ,  Alex Phillipou  1 ,  Inmaculada Rioja  1 ,  Rishi R Shah  1 ,  Christopher R Wellaway  1 ,  Rab K Prinjha  1 ,  David S Palmer  2 ,  William J Kerr  2 ,  Marc Reid  2 ,  Ian D Wall  1 ,  Rosa Cookson  1
Affiliations
  • 1. GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • 2. Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
PMID: 37967462 DOI: 10.1021/acs.jmedchem.3c00906
Abstract

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

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