Probing the difference between BH3 groove of Mcl-1 and Bcl-2 protein: Implications for dual inhibitors design

Based on our previous discovery of a dual inhibitor of Mcl-1 and Bcl-2, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (1, S1), and guided by structure insight of 1 complex with Mcl-1 and Bcl-2, we exploited the spatial orientation of BH3 groove of the two proteins by a series of analogues of 1. These analogues contain substitutes with various steric hindrance designed to explore the width and length of the p2 pocket. The structure–activity relationships (SARs) studies together with docking studies and cell-based assays proved that the p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2. A novel dual inhibitor 6 was obtained based on these new findings that it exhibited nanomalar affinities toward Mcl-1 and Bcl-2, as well as nanomalar cytotoxicity activity against multiple cancer cell lines.

Predicted binding models of compound 3c (a) in complex with Mcl-1 (b) and Bcl-2 (c). The p1 and p2 pockets of Mcl-1 and Bcl-2 are labeled.Figure optionsDownload as PowerPoint slideHighlights
► We have synthesized two series dual inhibitors of Mcl-1 and Bcl-2.
► The spatial orientation of BH3 groove of the two proteins was exploited.
► The p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2.
► Compound 6 exhibits nanomalar affinities and nanomalar cytotoxicity activity.