Discovery of (R)-4-(8-methoxy-2-methyl-1-(1-phenylethy)-1H-imidazo[4,5-c]quinnolin-7-yl)-3,5-dimethylisoxazole as a potent and selective BET inhibitor for treatment of acute myeloid leukemia (AML) guided by FEP calculation

The functions of the bromodomain and extra terminal (BET) family of proteins have been proved to be involved in various diseases, particularly the acute myeloid leukemia (AML). In this work, guided by free energy perturbation (FEP) calculation, a methyl group was selected to be attached to the 1H-imidazo[4,5-c]quinoline skeleton, and a series of congeneric compounds were synthesized. Among them, compound 10 demonstrated outstanding activity against BRD4 BD1 with an IC50 value of 1.9 nM and exhibited remarkable antiproliferative effects against MV4-11 cells. The X-ray cocrystal structure proved that 10 occupied the acetylated lysine (KAc) binding cavity and the WPF shelf of BRD4 BD1. Additionally, 10 displayed high selectivity towards BET family members, effectively inhibiting the growth of AML cells, promoting apoptosis, and arresting the cell cycle at the G0/G1 phase. Further mechanistic studies demonstrated that compound 10 could suppress the expression of c-Myc and CDK6 while enhancing the expression of P21, PARP, and cleaved PARP. Moreover, 10 exhibited remarkable pharmacokinetic properties and significant antitumor efficacy in vivo. Therefore, compound 10 may represent a new, potent and selective BET bromodomain inhibitor for the development of therapeutics to treat AML.