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

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.