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用于癌症治疗的小分子细胞外信号调节激酶（ERK）抑制剂的研发。

Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy.

作者信息

Pan Xiaoli, Pei Junping, Wang Aoxue, Shuai Wen, Feng Lu, Bu Faqian, Zhu Yumeng, Zhang Lan, Wang Guan, Ouyang Liang

机构信息

State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.

Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.

出版信息

Acta Pharm Sin B. 2022 May;12(5):2171-2192. doi: 10.1016/j.apsb.2021.12.022. Epub 2022 Jan 4.

DOI:10.1016/j.apsb.2021.12.022
PMID:35646548
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9136582/
Abstract

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.

摘要

丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶1/2（ERK1/2）信号通路可被多种细胞外刺激广泛激活，其失调与癌细胞的增殖、侵袭和迁移有关。ERK1/2位于该信号通路的末端，很少发生突变，这使其成为抗癌药物开发的一个有吸引力的靶点。目前，越来越多的ERK1/2抑制剂被设计和合成用于抗肿瘤治疗，其中代表性化合物已进入临床试验阶段。当ERK1/2信号转导被消除时，ERK5可能提供一条旁路途径来挽救细胞增殖，并削弱ERK1/2抑制剂的效力。因此，针对ERK5或基于ERK5对ERK1/2的补偿机制进行药物研究为肿瘤治疗开辟了一条新途径。本文综述了ERK的生理和生物学功能，重点关注靶向ERK的小分子抑制剂的构效关系，以期为未来药物设计和优化提供指导，并讨论克服耐药性的潜在治疗策略。

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