Discovery of Novel Mcl-1 Inhibitors with a 3-Substituted-1 H-indole-1-yl Moiety Binding to the P1-P3 Pockets to Induce Apoptosis in Acute Myeloid Leukemia Cells

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 1H-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 ¹⁵N-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.