Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl‑1 and Bfl‑1 Proteins

Anti-apoptotic Bcl-2
family proteins are overexpressed in a wide
spectrum of cancers and have become well validated therapeutic targets.
Cancer cells display survival dependence on individual or subsets
of anti-apoptotic proteins that could be effectively targeted by multimodal
inhibitors. We designed a 2,5-substituted benzoic acid scaffold that
displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design
was guided by several solved cocrystal structures with Mcl-1, leading
to the development of compound 24, which binds both Mcl-1
and Bfl-1 with Ki values of 100 nM and
shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding
profile of 24 was translated to on-target cellular activity
in model lymphoma cell lines. These studies lay a foundation for developing
more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide
greater single agent efficacy and broader coverage to combat resistance
in several types of cancer than selective Mcl-1 inhibitors alone.