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protein tyrosine phosphatase non-receptor type 11

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 3203

Nomenclature: protein tyrosine phosphatase non-receptor type 11

Abbreviated Name: SHP2

Family: Protein tyrosine phosphatases non-receptor type (PTPN)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 593 12q24.13 PTPN11 protein tyrosine phosphatase non-receptor type 11
Previous and Unofficial Names Click here for help
Noonan syndrome 1 (NS1) | SH2 domain-containing protein tyrosine phosphatase 2 | SHP-2 | src homology region 2 domain phosphatase | Src homology-2 domain-containing phosphatase Shp2
Database Links Click here for help
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Enzyme Reaction Click here for help
EC Number: 3.1.3.48

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
batoprotafib Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.0 pIC50 3
pIC50 8.0 (IC50 1.1x10-8 M) [3]
vociprotafib Small molecule or natural product Hs Inhibition - - 2
[2]
Inhibitor Comments
Other SHP2 inhibitors (whose structures have not yet been disclosed) include BBP-398 (formerly IACS-15509; Navire Pharma; phase 1) and JAB-3312 (Jacobio Pharmaceuticals; phase 1/2).
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
migoprotafib Small molecule or natural product Ligand has a PDB structure Hs Inhibition >6.8 – 9.0 pIC50 5
pIC50 >9.0 (IC50 <1x10-9 M) [5]
Description: Measuring dephosphorylation catalysed by wild type SHP2 in a biochemical assay
pIC50 6.8 (IC50 1.7x10-7 M) [5]
Description: Measuring dephosphorylation catalysed by SHP2E76K in a biochemical assay
Immunopharmacology Comments
SHP2 regulates programmed cell death 1 (PD-1)-mediated signal transduction and it is therefore involved in immune checkpoint modulation.
General Comments
Src homology-2 domain-containing phosphatase SHP2 is encoded by the PTPN11 gene. It is a cytosolic protein-tyrosine phosphatase whose activity opposes the action of protein kinases that phosphorylate tyrosine residues on receptors for growth factors and cytokines [1]. SHP2 promotes activation of the RAS-MAPK-ERK signalling pathway and it participates in the PD-1/PD-L1 pathway that regulates immune surveillance. It represents a potential new target for the treatment of cancer [4] and other human diseases that are 1) driven by gain-of-function mutations and/or over-expression of receptor tyrosine kinases, or 2) the result of mutations in PTPN11 that have been identified in certain cancers and congenital disorders. Mutations in PTPN11 cause Noonan syndrome 1 and LEOPARD syndrome.
Small molecule SHP2 inhibitors are being investigated for clinical applications, primarily to block dysregulated RAS-MAPK-ERK signalling in advanced solid tumours, and also for potential to enhance the efficacy of anti-PD-1/PD-L1-based immunotherapies, RTK inhibitors or direct KRAS inhibitors.

References

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1. Grossmann KS, Rosário M, Birchmeier C, Birchmeier W. (2010) The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res, 106: 53-89. [PMID:20399956]

2. Jogalekar A, Won W, Koltun ES, Gill A, Mellem K, Aay N, Buckl A, Semko C, Kiss G. (2018) 2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric shp2 inhibitors. Patent number: WO2018013597A1. Assignee: Revolution Medicines, Inc.. Priority date: 12/07/2016. Publication date: 18/01/2018.

3. LaMarche MJ, Acker M, Argintaru A, Bauer D, Boisclair J, Chan H, Chen CH, Chen YN, Chen Z, Deng Z et al.. (2020) Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. J Med Chem, 63 (22): 13578-13594. [PMID:32910655]

4. Mohi MG, Neel BG. (2007) The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev, 17 (1): 23-30. [PMID:17227708]

5. Taylor AM, Williams BR, Giordanetto F, Kelley EH, Lescarbeau A, Shortsleeves K, Tang Y, Walters WP, Arrazate A, Bowman C et al.. (2023) Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors. J Med Chem, 66 (19): 13384-13399. [PMID:37774359]

How to cite this page

Protein tyrosine phosphatases non-receptor type (PTPN): protein tyrosine phosphatase non-receptor type 11. Last modified on 23/10/2023. Accessed on 24/05/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3203.