Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer.
Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer.
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MEK1/2抑制剂和降解剂在癌症治疗中的研究进展
DOI：
10.1016/j.ejmech.2021.113386
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发表时间：
2021-03
影响因子：
6.7
通讯作者：
Ping Xu
中科院分区：
文献类型：
--
作者：
Chao Wang;Han Wang;Cangxin Zheng;Zhenming Liu;Xiaozuo Gao;Fengrong Xu;Yan Niu;Liangren Zhang;Ping Xu
丝裂原激活蛋白激酶激酶 1 和 2 (MEK1/2) 是 RAS-RAF-MEK-ERK 通路（或 ERK 通路）的重要组成部分，参与多种细胞过程的调节，包括增殖、存活和分化等。以MEK为靶点已成为癌症治疗的重要策略，迄今为止FDA已批准4种MEK抑制剂（MEKis）。然而，由于长期治疗下产生耐药性，MEKs的应用受到限制。幸运的是，一种名为蛋白水解靶向嵌合体 (PROTAC) 的新兴技术可以通过诱导 MEK1/2 降解来突破这一限制。与 MEK 相比，MEK1/2 PROTAC 的研究很少，迄今为止仅报道了三种 MEK1/2 PROTAC 分子。本文将概述ERK通路以及MEK1/2抑制剂的作用机制和研究进展，但重点关注MEK降解剂的开发及其优化策略。随后将讨论可间接诱导MEK降解的PAC-1策略、ERK途径上的其他PROTAC、PROTAC技术的优势和挑战。
Mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) are the crucial part of the RAS-RAF-MEK-ERK pathway (or ERK pathway), which is involved in the regulation of various cellular processes including proliferation, survival, and differentiation et al. Targeting MEK has become an important strategy for cancer therapy, and 4 MEK inhibitors (MEKis) have been approved by FDA to date. However, the application of MEKis is limited due to acquired resistance under long-term treatment. Fortunately, an emerging technology, named proteolysis targeting chimera (PROTAC), could break through this limitation by inducing MEK1/2 degradation. Compared to MEKis, MEK1/2 PROTAC is rarely studied and only three MEK1/2 PROTAC molecules, have been reported until now. This paper will outline the ERK pathway and the mechanism and research progress of MEK1/2 inhibitors, but focus on the development of MEK degraders and their optimization strategies. PAC-1 strategy which can induce MEK degradation indirectly, other PROTACs on ERK pathway, the advantages and challenges of PROTAC technology will be subsequently discussed.
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影响因子：
8.6
作者：
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影响因子：
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影响因子：
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影响因子：
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