Small-molecule Modulators Targeting SHP2 for Cancer Therapy

Anticancer Agents Med Chem. 2023;23(5):498-504. doi: 10.2174/1871520622666220921093052.

Abstract

Background: SHP2 is a protein tyrosine phosphatase that is extensively involved in several signaling pathways related to cancer occurrence, and thus SHP2 has been proposed as an attractive target for cancer treatment.

Methods: After a brief introduction of SHP2, we provided a short overview of the structure, function and regulation mechanism of SHP2 in cancer occurrence. Then, this perspective focused on the current therapeutic strategies targeting SHP2, including SHP2 PTP inhibitors, SHP2 allosteric inhibitors and SHP2-targeting PROTACs, and discussed the benefits and defects of these strategies. Finally, the opportunities and challenges were presented.

Results: SHP2 regulated RAS-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 signaling pathways involved in the pathogenesis of cancer via conformations conversion. Current therapeutic strategies targeting SHP2, especially SHP2 allosteric inhibitors, hold significant potency and have broad application prospects for cancer therapy.

Conclusion: In summary, SHP2 is a promising therapeutic target, and strategies targeting SHP2 offer an alternative program for cancer patients.

Keywords: PROTACs; SHP2; SHP2 PTP inhibitors; SHP2 allosteric inhibitors; cancer treatment; phosphatase.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors* / chemistry
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Signal Transduction

Substances

  • Enzyme Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • PTPN11 protein, human