Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors. Issue 22 (12th June 2021)

• Record Type: Journal Article
• Authors: Guo, Yu; Xu, Yaping; Dong, Xiaowu; Zhang, Jianjun
• Is Part Of: ChemistrySelect. Volume 6:Issue 22(2021)
• Page Start: 5504
• Page End: 5523
• Publication Date: 2021-06-12
• Subjects: Allosterism -- Cancer -- Catalytic site -- Protein tyrosine phosphatase -- SHP2 inhibitor; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.202100186
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: 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. Abstract : SHP2 is a special protein tyrosine phosphatase (PTP), which is of great concern due to its key role in cancer‐related pathways. Because of the difficulties in targeting catalytic site, the development of SHP2 inhibitors has been in a dilemma. Until recently, researchers finally crossed the undruggable barrier of SHP2 through an allosteric 'tunnel', ushering in a new era of SHP2 inhibitor development. We will review in this order, hoping to provide inspiration for the development of SHP2 as well as PTPs inhibitors.