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