Lead optimization of (CG13250), a quinolin-2(1)-one-based inhibitor of the BRD4 member of the bromodomain and extraterminal (BET) family of proteins.

The inhibition of the BET BRD4 protein has rapidly emerged as an indirect means of inhibiting the intrinsically disordered c-Myc proto-oncoprotein, a "holy grail" in oncology. Herein, we conducted lead optimization of , a potent BRD4 inhibitor previously discovered by our group. Several compounds exhibited single-digit nanomolar binding affinities, largely mirrored by sub-micromolar GIs in the MV4;11 acute myeloid leukemia cell line. Additionally, we solved a co-crystal structure of the first bromodomain of BRD4 with . In general, the co-crystal structure rationalized our structure-activity relationship data, and will inform future inhibitor design. Finally, we identified a selection of potent compounds that are suitable for further preclinical evaluation.