Discovery of Novel Mcl-1 Inhibitors with a 3-Substituted-1<i>H</i>-indole-1-yl Moiety Binding to the P1–P3 Pockets to Induce Apoptosis in Acute Myeloid Leukemia Cells
Hongguang Deng, Jingyi Zhang, Liang Liu, Hong Zhang, Yu Han, Linlin Wu, Yongkui Jing, Min Huang, Linxiang Zhao
Abstract
Mcl-1 is a main antiapoptotic protein in acute myeloid leukemia (AML) and is used as a target to develop inhibitors. Currently, potent Mcl-1 inhibitors primarily interact with the P2–P4 pockets of Mcl-1, but pharmacological modulation by targeting the P1 pocket is less explored. We designed a series of 1 H -indole-2-carboxylic acid compounds as novel Mcl-1 inhibitors occupying the P1–P3 pockets and evaluated their Mcl-1 inhibition and apoptosis induction in AML cells. Two-dimensional 15 N-HSQC spectroscopy indicated that 47 ( K i = 24 nM) bound to the BH3 binding groove, occupied the P1 pocket in Mcl-1, and formed interactions with Lys234 and Val249. 47 exhibited good microsomal stability and pharmacokinetic profiles, with low potential risk of cardiotoxicity. 47 inhibited tumor growth in HL-60 and THP-1 xenograft models with growth inhibition rate of 63.7% and 57.4%, respectively. Collectively, 47 represents a novel Mcl-1 inhibitor targeting the P1–P3 pockets with excellent antileukemia effects.