Medicinal chemistry strategies for the development of protein tyrosine phosphatase SHP2 inhibitors and PROTAC degraders.

As a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) is involved in mitogen-activated protein kinase (MAPK) signaling pathway and contributes to immune surveillance via programmed cell death pathway (PD-1/PD-L1). To date, numerous SHP2 inhibitors have been developed, some of them have advanced into clinical trials. Moreover, the first PROTAC degrader SHP2-D26 has been proved to effectively induce degradation of SHP2, which may open a new avenue for targeted SHP2 therapies. In this review, we systematically summarized the development of SHP2 inhibitors with a particular focus on the structure-activity relationships (SAR) studies, crystal structures or binding models, and their modes of action.