BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

TLDR: An easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold is reported, which is highly selective for the BET family of bromodomains and highlights the importance of the substitution of the uracil moiety for potency and selectivity.

Abstract: Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains Structure–activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure–activity data An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement Given these findings, novel and easily synth