Structure-based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors

摘要

Small-molecule inhibitors of Bromodomain and Extra Terminal proteins (BET), including BRD2, BRD3 and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis and evaluation of γ-carboline-containing compounds as a new class of small molecule BET inhibitors. The most potent inhibitor (compound >18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3 and BRD4) with Ki values of 3.2–24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound >18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a co-crystal structure of >18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound’s high binding affinity and for its further structure-based optimization. Compound >18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.