Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy

Abstract

The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy, while the multifaceted roles of SHP2 complicate the drug discovery targeting SHP2. Given the biological significance of SHP2, strategies targeting SHP2 have been developed in recent years. To date, eight SHP2 inhibitors have advanced into clinical trials as mono- or combined therapy for treating solid tumors or adaptive resistant cancers. In this Perspective, we briefly summarize the strategies targeting SHP2 including inhibitors, activators, and proteolysis-targeting chimera (PROTAC) degraders. Besides, targeting the protein–protein interactions between SHP2 and other adaptor proteins is also discussed. Finally, we also highlight the target- and pathway-dependent combination strategies of SHP2 for cancer therapy. This Perspective may provide a timely and updated overview on the strategies targeting SHP2 for cancer therapy.

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

“…Several SHP2 inhibitors have been developed and are well discussed elsewhere; 36 , 248 – 254 some of them have advanced to clinical trials. 253 The most popular SHP2 inhibitors are catalytic activity inhibitors that target the PTP catalytic pocket, allosteric inhibitors that bind to a region outside the PTP catalytic pocket and maintain SHP2 in its autoinhibited conformation, 36 , 255 and SHP2 Proteolysis Targeting Chimera (PROTAC) molecules 251 (Fig.…”

Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

“…In addition to SHP2 inhibitors, PROTAC‐based SHP2 degrades, including SHP2‐D26, SP4, ZB‐S‐29, and R1‐5C, also represent a promising therapeutic strategy for various diseases, especially mutation‐driven cancer 71 . PROTAC degraders are designed by tethering the solvent exposed region of inhibitor and an E3 ubiquitin ligase ligand via a linker, which could induce target protein degradation 72 …”

“…In addition to SHP2 inhibitors, PROTAC-based SHP2 degrades, including SHP2-D26, SP4, ZB-S-29, and R1-5C, also represent a promising therapeutic strategy for various diseases, especially mutation-driven cancer. 71 The acetyl group in compound 12 (SHP2 WT IC 50 = 98.7 nM) was exposed to the solvent and then tethered to the VHL-1 ligand via different length linkers, generating a series of SHP2 degraders (Figure 16). Among them, SHP2-D26 achieved excellent degradation of SHP2 (DC 50 = 6.0 nM in KYSE520 cells; DC 50 = 2.6 nM in MV4; 11 cells).…”

The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?

“…SHP2/Shp2 proteins are highly conserved along the Vertebrate subphylum (>80% identity, >95% among mammals), and orthologs are found in non-vertebrates, notably insects (Corskrew/CSW in D. melanogaster ) and roundworms (PTP-2 in C. elegans ). SHP2 is composed of two N-terminal SH2 domains (N-SH2 and C-SH2) able to interact with phosphotyrosine-containing molecules, a C-terminal domain containing phosphorylation sites and a protein/protein interaction motif with regulatory functions, and a central PTP catalytic domain carrying a canonical PTP signature motif (C(X) 5 R), that dephosphorylates specific phosphotyrosines [ 1 , 2 ]. Recent biochemical studies, as well as machine learning approaches, directed towards the identification of SHP2′ substrate specificity, revealed an enrichment of acidic residues upstream from the phosphotyrosine [ 3 , 4 ].…”