Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors
Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors
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蛋白酪氨酸磷酸酶SHP2抑制剂的发现新进展
DOI：
10.1039/d1md00386k
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Long Ya-Qiu
中科院分区：
文献类型：
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作者：
Kong Jiao;Long Ya-Qiu
Src homology 2 domain-containing protein tyrosine phosphatase（SHP 2）是由Ptpn 11基因编码的一种非受体蛋白酪氨酸磷酸酶，通过调节RAS/ERK信号通路等多种信号通路来调控细胞生长、分化和凋亡，并参与PD-1/PD-L1免疫监视通路。它已被认为是一个突破性的抗肿瘤治疗靶点。此外，大量研究表明，SHP 2在炎症性疾病的调节中起着重要作用。然而，靶向SHP 2活性位点的抑制剂由于其低选择性和低生物利用度而缺乏药物相似性，因此没有一种药物进入临床开发。近年来，稳定SHP 2非活性构象的变构抑制剂研究取得了突破性进展，为SHP 2作为抗肿瘤药物靶点的可药用性提供了临床依据。本文综述了近年来SHP 2小分子抑制剂的设计和发现，重点介绍了几种具有代表性的SHP 2抑制剂的构效关系（SAR）分析，概述了以SHP 2为靶点的小分子抑制剂的研究进展和治疗潜力。
Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the Ptpn11 gene, which regulates cell growth, differentiation and apoptosis via modulating various signaling pathways, such as the RAS/ERK signaling pathway, and participates in the PD-1/PD-L1 pathway governing immune surveillance. It has been recognized as a breakthrough antitumor therapeutic target. Besides, numerous studies have shown that SHP2 plays an important role in the regulation of inflammatory diseases. However, inhibitors targeting the active site of SHP2 lack drug-likeness due to their low selectivity and poor bioavailability, thus none has advanced to clinical development. Recently, allosteric inhibitors that stabilize the inactive conformation of SHP2 have achieved breakthrough progress, providing the clinical proof for the druggability of SHP2 as an antitumor drug target. This paper reviews the recently reported design and discovery of SHP2 small molecule inhibitors, focused on the structure–activity relationship (SAR) analysis of several representative SHP2 inhibitors, outlining the evolution and therapeutic potential of the small molecule inhibitors targeting SHP2.