Discovery of a Copper-Based Mcl-1 Inhibitor as an Effective Antitumor Agent.
Discovery of a Copper-Based Mcl-1 Inhibitor as an Effective Antitumor Agent.
复制标题
铜基Mcl-1抑制剂作为有效抗肿瘤剂的发现。
DOI：
10.1021/acs.jmedchem.9b02047
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发表时间：
2020-08
影响因子：
7.3
通讯作者：
Xing Lu;Yan-cheng Liu;C. Orvig;H. Liang;Zhenfeng Chen
中科院分区：
文献类型：
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作者：
Xing Lu;Yan-cheng Liu;C. Orvig;H. Liang;Zhenfeng Chen
髓样细胞白血病1(Mcl-1)是一种重要的肿瘤细胞生存调节因子，属于凋亡相关蛋白Bcl2家族。到目前为止，几乎没有报道过类似Mcl-1的药物抑制剂。在这里，我们报道了10个9-取代的β-Caroline配体的铜配合物的制备，它们作为金属基的Mcl-1抑制剂。化合物14是一种高效、选择性的Mcl-1抑制剂，具有较强的体外抗肿瘤活性。机制研究表明，络合物14破坏Mcl-1-Bax/Bak异二聚化，诱导Bax/Bak依赖的细胞凋亡。此外，在NCI-H460异种移植模型中，化合物14显著(P<；0.001)抑制体内肿瘤生长，诱导肿瘤坏死，并延长存活时间。此外，化合物14对小鼠无明显毒性。综上所述，这些发现表明，化合物14是一种基于铜的Mcl-1抑制剂，具有高效、低毒的特点，有望被开发用于Mcl-1相关癌症的治疗。
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.