Version 2 2023-11-17, 22:29Version 2 2023-11-17, 22:29
Version 1 2023-11-15, 22:20Version 1 2023-11-15, 22:20
journal contribution
posted on 2023-11-17, 22:29authored byErin Bradley, Lucia Fusani, Chun-wa Chung, Peter D. Craggs, Emmanuel H. Demont, Philip G. Humphreys, Darren J. Mitchell, Alex Phillipou, Inmaculada Rioja, Rishi R. Shah, Christopher R. Wellaway, Rab K. Prinjha, David S. Palmer, William J. Kerr, Marc Reid, Ian D. Wall, Rosa Cookson
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.