Abstract
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 5jc21, a potent BRD4 inhibitor previously discovered by our group. Several compounds exhibited single-digit nanomolar K (d) binding affinities, largely mirrored by sub-micromolar GI(50)s in the MV4;11 acute myeloid leukemia cell line. Additionally, we solved a co-crystal structure of the first bromodomain of BRD4 with 5jc21. 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.