School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100000, China.
J Med Chem. 2022 Feb 24;65(4):3066-3079. doi: 10.1021/acs.jmedchem.1c02008. Epub 2022 Feb 14.
The protein tyrosine phosphatase SHP2 encoded by is a promising therapeutic target for cancer therapy, while the multifaceted roles of SHP2 complicate the drug discovery targeting SHP2. Given the biological significance of SHP2, strategies targeting SHP2 have been developed in recent years. To date, eight SHP2 inhibitors have advanced into clinical trials as mono- or combined therapy for treating solid tumors or adaptive resistant cancers. In this Perspective, we briefly summarize the strategies targeting SHP2 including inhibitors, activators, and proteolysis-targeting chimera (PROTAC) degraders. Besides, targeting the protein-protein interactions between SHP2 and other adaptor proteins is also discussed. Finally, we also highlight the target- and pathway-dependent combination strategies of SHP2 for cancer therapy. This Perspective may provide a timely and updated overview on the strategies targeting SHP2 for cancer therapy.
由 编码的蛋白酪氨酸磷酸酶 SHP2 是癌症治疗有前途的治疗靶点，而 SHP2 的多方面作用使针对 SHP2 的药物发现复杂化。鉴于 SHP2 的生物学意义，近年来已经开发出针对 SHP2 的策略。迄今为止，已有八种 SHP2 抑制剂作为单药或联合疗法用于治疗实体瘤或适应性耐药癌症进入临床试验。在本观点中，我们简要总结了针对 SHP2 的策略，包括抑制剂、激活剂和蛋白水解靶向嵌合体（PROTAC）降解剂。此外，还讨论了靶向 SHP2 与其他衔接蛋白之间的蛋白质-蛋白质相互作用的策略。最后，我们还强调了 SHP2 用于癌症治疗的基于靶标和通路的组合策略。本观点可能为针对 SHP2 的癌症治疗策略提供及时和最新的概述。
