SHP2变构抑制剂的研究进展  

Research Progress in Allosteric SHP2 Inhibitors

作　　者：堵桐弘 吕遐师 赖宜生[1] 

机构地区：[1]中国药科大学新药研究中心,天然药物活性组分与药效国家重点实验室,江苏省代谢性疾病药物重点实验室,江苏 南京

出　　处：《药物化学》2022年第2期211-223,共13页Hans Journal of Medicinal Chemistry

摘　　要：蛋白酪氨酸磷酸酶在维持蛋白质酪氨酸磷酸化的稳态中起重要的调节作用。SHP2是首个被证实的致癌性蛋白酪氨酸磷酸酶,其信号失调与多种恶性肿瘤的发生发展密切相关。作为多条信号通路的交汇点,SHP2不仅影响肿瘤细胞的增殖、转移和侵袭等过程,并且还参与PD-1/PD-L1介导的肿瘤免疫逃逸,从多方面促进肿瘤的发生发展。因此SHP2被认为是一个理想的肿瘤干预靶标。然而,多年以来,人们为开发靶向SHP2的抗肿瘤药物付出了诸多努力,却收效甚微,为此SHP2曾一度被认为是“无药可及”的靶点。直至最近,以TNO155为代表的SHP2变构抑制剂相继进入临床开发,才为攻克这一极具挑战性的靶点带来希望。至今为止,已有13款SHP2变构抑制剂开展临床研究。本文简介SHP2的结构、功能及其与肿瘤的相关性,侧重综述近年来SHP2变构抑制剂的研发历程和临床试验的进展。Protein tyrosine phosphatase plays an important role in maintaining protein tyrosine phosphoryla-tion homeostasis. SHP2 is the first confirmed carcinogenic protein tyrosine phosphatase, whose dysregulation is closely related to the occurrence and development of a variety of malignant tu-mors. As the intersection of multiple signaling pathways, SHP2 not only affects the proliferation, metastasis and invasion of tumor cells, but also participates in PD-1/PD-L1-mediated tumor im-mune escape, promoting the occurrence and development of tumors in many aspects. Therefore, SHP2 has been considered as an ideal target for cancer intervention. However, over the years, ef-forts to develop anti-tumor drugs targeting SHP2 have had little success. Hence, SHP2 was once con-sidered as an “undruggable” target. It is only recently that the clinical development of allosteric SHP2 inhibitors, represented by TNO155, has brought hope for tackling this challenging target. So far, there have been 13 candidates in clinical trials. This review briefly introduces the structure and functions of SHP2 and its correlation with tumors, and focuses on the development process and clinical trial progress of allosteric SHP2 inhibitors in recent years.

关 键 词：蛋白酪氨酸磷酸酶 催化位点 变构位点 自抑制构象 变构抑制剂 

分 类 号：R914[医药卫生—药物化学]