Structure-Based Discovery and Optimization of Furo[3,2-<i>c</i>]pyridin-4(5<i>H</i>)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.

Abstract

Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-<i>c</i>]pyridin-4(5<i>H</i>)-one derivatives as novel BD2-selective BET inhibitors. The representative compound <b>8l</b> (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC₅₀) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, <b>8l</b> exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound <b>8l</b> displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC₅₀ = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. <b>8l</b> also demonstrated good metabolic stability in vitro. These data indicate that <b>8l</b> may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).