Discovery of a Copper-Based Mcl‑1 Inhibitor as an Effective Antitumor Agent

Myeloid cell leukemia 1 (Mcl-1), which belongs to the Bcl-2 family of prosurvival proteins, is a key regulator of cancer cell survival. To date, few drug-like Mcl-1 inhibitors have been reported. Herein, we report the preparation of 10 copper complexes with 9-substituted β-carboline ligands that act as metal-based Mcl-1 inhibitors. Complex <b>14</b> was identified as a potent and selective Mcl-1 inhibitor with strong <i>in vitro</i> antitumor activity. Mechanistic studies demonstrated that complex <b>14</b> disrupted Mcl-1-Bax/Bak heterodimerization and induced Bax/Bak-dependent apoptosis. In addition, complex <b>14</b> significantly (<i>P</i> < 0.001) inhibited tumor growth <i>in vivo</i>, induced tumor necrosis, and extended survival time in an NCI-H460 xenograft model. Furthermore, complex <b>14</b> showed no apparent toxicity in mice. Together, these findings indicate that complex <b>14</b> is a copper-based Mcl-1 inhibitor with high efficacy and low toxicity that could be developed for the treatment of Mcl-1-related cancers.