Discovery and structure-activity relationship studies of novel Bcl-2/Mcl-1 dual inhibitors with indole scaffold.

ABSTRACT

The Bcl-2 anti-apoptotic proteins were widely overexpressed in diverse tumor cells, especially for Bcl-2 and Mcl-1, which regarding as important targets of apoptosis induction and resistance of chemotherapy. We identified novel Bcl-2/Mcl-1 dual inhibitors with indole scaffold by the optimization of hit 1. Structure modification against several moieties including hydrophobic fragment, side chain and benzoic acid fragment was conducted and the structure-activity relationship was analyzed. The representative compound 12f exhibited sub-micromolar binding affinities to Bcl-2/Mcl-1 without binding affinity to Bcl-XL. Mechanism of action studies suggested that compound 12f dose-dependently triggered apoptosis in HL-60 cells. Compound 12f represents a novel Bcl-2/Mcl-1 dual inhibitor which deserving further study.