Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical trials
- PMID: 34403682
- DOI: 10.1016/j.pharmthera.2021.107966
Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical trials
Abstract
Phosphorylation is a reversible post-translational modification regulated by phosphorylase and dephosphorylase to mediate important cellular events. Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by PTPN11 is the first identified oncogenic protein in protein tyrosine phosphatases family. Serving as a convergent node, SHP2 is involved in multiple cascade signaling pathways including Ras-Raf-MEK-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 pathways. Especially, the double-edged roles of SHP2 based on the substrate specificity in various biological contexts dramatically increase the effect complexity in different SHP2-associated diseases. Evidences suggest that by collaborating with other mutations in associated pathways, dysregulation of SHP2 contributes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer treatment. SHP2 can either act as oncogenic factor or tumor suppressor in different diseases, and both the conserved catalytic dephosphorylation mechanism and the unique allosteric regulation mechanism of SHP2 provide opportunities for the development of SHP2 inhibitors and activators. To date, several small-molecule SHP2 inhibitors have advanced into clinical trials for mono- or combined therapy of cancers. Moreover, SHP2 activators and proteolysis-targeting chimera (PROTAC)-based degraders also display therapeutic promise. In this review, we comprehensively summarize the overall structures, regulation mechanisms, double-edged roles of SHP2 in both physiological and carcinogenic pathways, and SHP2 inhibitors in clinical trials. SHP2 activators and degraders are also briefly discussed. This review aims to provide in-depth understanding of the biological roles of SHP2 and highlight therapeutic potential of targeting SHP2.
Keywords: Allosteric regulation; Cancer therapy; Dephosphorylase; Oncogenic protein; Protein tyrosine phosphatase; SHP2 inhibitors; Tumor suppressor.
Copyright © 2021 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors declare that there are no conflicts of interest.
Similar articles
-
Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy?Front Immunol. 2024 Mar 5;15:1340726. doi: 10.3389/fimmu.2024.1340726. eCollection 2024. Front Immunol. 2024. PMID: 38504984 Free PMC article. Review.
-
Small-molecule Modulators Targeting SHP2 for Cancer Therapy.Anticancer Agents Med Chem. 2023;23(5):498-504. doi: 10.2174/1871520622666220921093052. Anticancer Agents Med Chem. 2023. PMID: 36154594 Review.
-
A comprehensive review of SHP2 and its role in cancer.Cell Oncol (Dordr). 2022 Oct;45(5):729-753. doi: 10.1007/s13402-022-00698-1. Epub 2022 Sep 6. Cell Oncol (Dordr). 2022. PMID: 36066752 Review.
-
Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.J Med Chem. 2022 Feb 24;65(4):3066-3079. doi: 10.1021/acs.jmedchem.1c02008. Epub 2022 Feb 14. J Med Chem. 2022. PMID: 35157464 Review.
-
Recent Advances of SHP2 Inhibitors in Cancer Therapy: Current Development and Clinical Application.J Med Chem. 2020 Oct 22;63(20):11368-11396. doi: 10.1021/acs.jmedchem.0c00249. Epub 2020 Jun 10. J Med Chem. 2020. PMID: 32460492 Review.
Cited by
-
Pepsinogen C Interacts with IQGAP1 to Inhibit the Metastasis of Gastric Cancer Cells by Suppressing Rho-GTPase Pathway.Cancers (Basel). 2024 May 8;16(10):1796. doi: 10.3390/cancers16101796. Cancers (Basel). 2024. PMID: 38791874 Free PMC article.
-
Discovery of a novel SHP2 allosteric inhibitor using virtual screening, FMO calculation, and molecular dynamic simulation.J Mol Model. 2024 Apr 13;30(5):131. doi: 10.1007/s00894-024-05935-y. J Mol Model. 2024. PMID: 38613643
-
Tyrosine phosphatase SHP2 aggravates tumor progression and glycolysis by dephosphorylating PKM2 in gastric cancer.MedComm (2020). 2024 Apr 4;5(4):e527. doi: 10.1002/mco2.527. eCollection 2024 Apr. MedComm (2020). 2024. PMID: 38576457 Free PMC article.
-
Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy?Front Immunol. 2024 Mar 5;15:1340726. doi: 10.3389/fimmu.2024.1340726. eCollection 2024. Front Immunol. 2024. PMID: 38504984 Free PMC article. Review.
-
Targeting Protein Phosphatases for the Treatment of Chronic Liver Disease.Curr Drug Targets. 2024;25(3):171-189. doi: 10.2174/0113894501278886231221092522. Curr Drug Targets. 2024. PMID: 38213163 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous