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Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors
Author(s) -
Guo Yu,
Xu Yaping,
Dong Xiaowu,
Zhang Jianjun
Publication year - 2021
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202100186
Subject(s) - allosteric regulation , protein tyrosine phosphatase , proto oncogene tyrosine protein kinase src , ptpn11 , sh2 domain , phosphatase , chemistry , small molecule , enzyme , active site , biochemistry , computational biology , biology , phosphorylation , gene , mutation , kras
SHP2 (Src homology‐2 domain‐containing protein tyrosine phosphatase‐2) is a unique protein tyrosine phosphatase(PTP)encoded by the PTPN11 gene, which is composed of two SH2 domains (N‐SH2, C‐SH2) and the PTP domain. SHP2 is essential in several oncogenic signaling pathways (especially Ras/Raf/MAPK) and has a wide range of mutations in various cancers. Therefore, the development of inhibitors of SHP2 has become the focus of anticancer research in recent years. Initially, the researchers hoped to directly inhibit SHP2 activity by targeting its catalytic sites like other PTP inhibitors’ development. However, the high homology and strong positivity of PTP catalytic sites bring great difficulties in developing such inhibitors. Finally, in 2015, a compact molecule (SHP099) passed the undruggable barrier of SHP2 through the allosteric tunnel. In this paper, the development of SHP2 inhibitors in recent years will be reviewed to transition from catalytic site inhibitors to allosteric inhibitors to provide suggestions for the development and application of SHP2 inhibitors and other PTP inhibitors.