Discovery and lead identification of quinazoline-based BRD4 inhibitors

[Display omitted] •Quinazoline can serve as a novel core structure in the design of potent BRD4 inhibitors.•N-Methyl 2-pyridone is a viable alternative to 3,5-dimethylisoxazole.•Combination of pyrazole and phenylmorpholine substitutions improved pharmacokinetics. A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.