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

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.

Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787

“…Acetylated piperidine ( S )-75 was the most potent compound accessed in the series to date, both from a biochemical and a hWB perspective. Interestingly, ( S )-75 was 100-fold more active at BRD4 BD1 over BRD4 BD2, consistent with what had been observed with the same chiral piperidine substituent on the previously prosecuted benzimidazole series . While the compound had desirable levels of FaSSIF solubility, the passive permeability of 10 nm/s highlighted a risk that oral bioavailability would be limited.…”