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

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Abstract
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 ten copper complexes with 9-substituted β-carboline ligands that act as metal-based Mcl-1 inhibitors. Complex 14 was identified as a potent and selective Mcl-1 inhibitor with strong in vitro antitumor activity. Mechanistic studies demonstrated that complex 14 disrupted Mcl-1-Bax/Bak heterodimerization and induced Bax/Bak-dependent apoptosis. In addition, complex 14 significantly (P<0.001) inhibited tumor growth in vivo, induced tumor necrosis, and extended survival time in an NCI-H460 xenograft model. Furthermore, complex 14 showed no apparent toxicity in mice. Together, these findings indicate that complex 14 is a copper-based Mcl-1 inhibitor with high efficacy and low toxicity that may be able to be developed for the treatment of Mcl-1-related cancers.
Funding Information
  • Ministry of Education of the People's Republic of China (IRT_16R15)
  • Natural Science Foundation of Guangxi Province (2016GXNSFGA380005, AD17129007)
  • National Natural Science Foundation of China (21431001, 81473102)
  • Guangxi Graduate Education (YCBZ2017029)

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