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

Pan-bromodomain and extra terminal (Pan-BET)inhibitors show profound efficacy but exhibit pharmacology-driventoxicities in clinical trials. The development of domain-selectiveBET inhibitors to separate efficacy and toxicity is urgently needed.Herein, we report a series of furo[3,2-c]pyridin-4(5H)-onederivatives as novel BD2-selective BET inhibitors. The representa-tive compound8l(XY153) potently bound to BRD4 BD2 with anhalf-maximum inhibitory concentration (IC50) value of 0.79 nMand displayed 354-fold selectivity over BRD4 BD1. Besides,8lexhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2domains. Compound8ldisplayed potent antiproliferative activityagainst multiple tumor cell lines, especially MV4-11 (IC50= 0.55nM), while showing weak cytotoxicity against the normal lungfibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors.8lalso demonstrated good metabolic stability invitro. These data indicate that8lmay serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML)