Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents
Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents
复制标题
小分子 Mcl-1 抑制剂：新兴抗肿瘤药物
DOI：
10.1016/j.ejmech.2018.01.076
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发表时间：
2018
影响因子：
6.7
通讯作者：
Fang Hao
中科院分区：
文献类型：
--
作者：
Wan Yichao;Dai Ningning;Tang Zilong;Fang Hao
B-cell lymphoma-2（Bcl-2）蛋白家族的抗凋亡成员，如Bcl-2和髓样细胞白血病-1（Myeloid cell leukemia-1，Mcl-1），是内源性凋亡途径的关键调节因子，在许多肿瘤细胞中过表达，已被证实为潜在的肿瘤药物靶点。许多Bcl-2蛋白抑制剂已被开发并进行临床试验，但没有Mcl-1抑制剂在临床上出现。此外，Mcl-1是对放疗和化疗产生抗性的重要原因，包括靶向其他Bcl-2家族成员的抑制剂。例如，最近推出的Bcl-2选择性抑制剂ABT-199在慢性淋巴细胞白血病（CLL）的治疗中显示出高效，但它不能在某些肿瘤细胞系中诱导由Mcl-1控制的凋亡。因此，开发有效的Mcl-1抑制剂成为临床治疗的迫切需要。本文简要介绍了Mcl-1蛋白的结构、在癌症中的作用，并重点介绍了2012 - 2017年Mcl-1小分子抑制剂的研究进展。
The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.