State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, P. R. China.
Department of Chemistry, Faculty of Science, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T1Z1, Canada.
J Med Chem. 2020 Sep 10;63(17):9154-9167. doi: 10.1021/acs.jmedchem.9b02047. Epub 2020 Aug 28.
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 was identified as a potent and selective Mcl-1 inhibitor with strong antitumor activity. Mechanistic studies demonstrated that complex disrupted Mcl-1-Bax/Bak heterodimerization and induced Bax/Bak-dependent apoptosis. In addition, complex significantly ( < 0.001) inhibited tumor growth , induced tumor necrosis, and extended survival time in an NCI-H460 xenograft model. Furthermore, complex showed no apparent toxicity in mice. Together, these findings indicate that complex 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.
髓系细胞白血病 1（Mcl-1）属于 Bcl-2 家族的生存蛋白，是癌细胞存活的关键调节剂。迄今为止，报道的类似药物的 Mcl-1 抑制剂很少。本文报道了 10 种带有 9 位取代β-咔啉配体的铜配合物的制备，这些配合物可作为基于金属的 Mcl-1 抑制剂。复合物 被鉴定为一种有效的、选择性的 Mcl-1 抑制剂，具有很强的抗肿瘤活性。机制研究表明，复合物 破坏了 Mcl-1-Bax/Bak 异二聚体的形成，并诱导了 Bax/Bak 依赖性凋亡。此外，复合物 显著（<0.001）抑制了 NCI-H460 异种移植模型中的肿瘤生长，诱导肿瘤坏死，并延长了存活时间。此外，复合物 在小鼠中没有明显的毒性。综上所述，这些发现表明，复合物 是一种高效低毒的基于铜的 Mcl-1 抑制剂，可用于治疗与 Mcl-1 相关的癌症。
