Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan -BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC 50 = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC 50 = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 ( 23 : 2583-fold; 10 : 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro . Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC 50 > 30 μM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with 10 (hERG IC 50 = 2.8 μM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.