Structure-based virtual screening, biological evaluation and biophysical study of novel Mcl-1 inhibitors.

Targeting the protein-protein interactions (PPIs) associated with Mcl-1 has become a promising therapeutic approach for cancer. Herein, we reported the discovery of novel Mcl-1 inhibitors using an integrated computational approach. Among 30 virtual screening hits, five compounds show inhibitory activities against Mcl-1. The most potent inhibitors (  = 5.4 μM) and ( = 0.53 μM) exhibit good selectivity against Bcl-2 and Bcl-xL. Compound exhibits anti-proliferation activity and induces caspase-3 activation in Jurkat cancer cells. Moreover, H⁄N HSQC NMR experiments suggested that compound likely binds in the P2 pocket of Mcl-1 and engages R263 in a salt bridge. Our study provides a good starting point for future discovery of more potent Mcl-1 selective inhibitors.