Small-Molecule and Peptide Inhibitors of the Pro-Survival Protein Mcl-1.
Small-Molecule and Peptide Inhibitors of the Pro-Survival Protein Mcl-1.
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DOI：
10.1002/cmdc.201500497
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发表时间：
2016-04-19
期刊：
影响因子：
3.4
通讯作者：
Howell LA
中科院分区：
文献类型：
--
作者：
Beekman AM;Howell LA
蛋白质-蛋白质相互作用以有益和有害的方式调节细胞过程的能力使它们成为明显的药物靶点。Bcl-2蛋白家族经历一系列蛋白质-蛋白质相互作用，调节内在细胞死亡途径。Bcl-2家族的促生存成员，包括Bcl-2，Bcl-xL和Mcl-1，通常在许多人类癌症中过表达。Bcl-2家族成员的有效调节剂已经开发出来并正在进行临床试验，但Mcl-1的有效调节在临床上仍然没有代表。此外，Mcl-1是对放射和化疗耐药的主要原因，包括靶向其他Bcl-2家族成员的抑制剂。随后，Mcl-1的抑制已成为科学界的重大兴趣。本文综述了迄今为止通过钉合肽和小分子调节Mcl-1活性所取得的进展。肽作为候选药物的发展，以及用于发现小分子的实验和计算技术的进步也得到了强调。
The ability of protein–protein interactions to regulate cellular processes in both beneficial and detrimental ways has made them obvious drug targets. The Bcl‐2 family of proteins undergo a series of protein–protein interactions which regulate the intrinsic cell‐death pathway. The pro‐survival members of the Bcl‐2 family, including Bcl‐2, Bcl‐xL, and Mcl‐1, are commonly overexpressed in a number of human cancers. Effective modulators of members of the Bcl‐2 family have been developed and are undergoing clinical trials, but the efficient modulation of Mcl‐1 is still not represented in the clinic. In addition, Mcl‐1 is a major cause of resistance to radio‐ and chemotherapies, including inhibitors that target other Bcl‐2 family members. Subsequently, the inhibition of Mcl‐1 has become of significant interest to the scientific community. This review covers the progress made to date in modulating the activity of Mcl‐1, by both stapled peptides and small molecules. The development of peptides as drug candidates, and the advancement of experimental and computational techniques used to discover small molecules are also highlighted.