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Download fileDiscovery of a Copper-Based Mcl‑1 Inhibitor as an Effective Antitumor Agent
journal contribution
posted on 2020-08-28, 16:11 authored by Xing Lu, Yan-Cheng Liu, Chris Orvig, Hong Liang, Zhen-Feng ChenMyeloid
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 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 could be developed for the treatment of Mcl-1-related cancers.
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NCI-H 460 xenograft modelcancer cell survivalMcl -1-Bax heterodimerizationprosurvival proteinstumor necrosisMcl -1-related cancersBcl -2 familyantitumor activityMechanistic studiesβ- carboline ligandsComplex 14Effective Antitumor Agent Myeloid c...10 copper complexesmetal-based Mclsurvival timetumor growthinhibitordrug-like Mcl