Design, Synthesis and Evaluation of a Novel Bcl-2/Mcl-1 Inhibitor

Bcl-2 and Mcl-1 are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. Structure-based drug design was utilized to develop a novel, 1-oxo-1H-phenalene-2,3-dicarbonitrile (OPD)-based small molecule inhibitor (S2) of Bcl-2/Mcl-1, which was synthesized readily by nucleophilic substitution reaction and click reaction. S2 exhibited potent binding capability to both Bcl-2 (Ki=0.60±0.20) and Mcl-1 (Ki=0.87±0.25 μM). Furthermore, S2 exhibited potent lethality on Hela cells.