Novel Mcl‐1/Bcl‐2 Dual Inhibitors Created by the Structure‐Based Hybridization of Drug‐Divided Building Blocks and a Fragment Deconstructed from a Known Two‐Face BH3 Mimetic

We have previously reported a small‐molecule two‐face Bim BH3 mimetic, 2,3‐dihydroxy‐6‐(4‐isopropylphenylthio)anthracene‐9,10‐dione ( 1 ). Herein, we linked a polyphenol fragment, which was deconstructed from compound 1 , with a drug‐derived building block gained from computer‐aided molecular design. 2‐Phenyl‐1 H ‐benzo[ d ]imidazole as a new scaffold for two‐face Bim mimetics was developed; based on this, a series of Mcl‐1/Bcl‐2 dual inhibitors were obtained. The most potent compound 6d binds to Mcl‐1 and Bcl‐2 with K i values of 127 and 607 nM, respectively, and effectively induces apoptosis in a dose‐dependent, mechanism‐based manner in multiple cancer cell lines.