9VRR

Crystal structure of human PTPN2 with inhibitor WS3

This is a non-PDB format compatible entry.

Summary for 9VRR

• Entry DOI: 10.2210/pdb9vrr/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 2, 5-[2-fluoranyl-4-[1-(3-methylbutyl)azetidin-3-yl]-6-oxidanyl-phenyl]-1,1-bis(oxidanylidene)-1,2,5-thiadiazolidin-3-one (3 entities in total)
• Functional Keywords: ptpn2, inhibitor, tumor immunity, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70722.11

Authors

Tong, C. (deposition date: 2025-07-07, release date: 2025-12-17)

Primary citation

Wang, D.,Song, M.,Tong, C.,Wang, W.,Li, Q.,Liu, J.,Chen, A.,Chen, Y.,Wang, L.,Hao, H.,Wang, X.,Han, K.,Xiao, Y.,Kuang, W.,Yang, P.
Development of Novel PTPN2/1 Inhibitors for the Treatment of Melanoma.
J.Med.Chem., 68:21917-21938, 2025

PubMed Abstract: The global incidence of melanoma has risen substantially over the past two decades, driving an urgent need for novel therapeutic strategies. The nonreceptor protein tyrosine phosphatases PTPN2/PTPN1 have emerged as promising therapeutic targets, yet developing effective inhibitors faces significant drug-like property challenges. Through rational drug design, we discovered ─a potent dual PTPN2/1 inhibitor exhibiting exceptional enzymatic activity (PTPN2 IC = 5.8 nM, PTPN1 IC = 12.8 nM), favorable safety profiles, and enhanced oral bioavailability (F = 7.1%). Mechanistic studies demonstrate that modulates the IFNγ-JAK-STAT signaling axis, significantly augmenting CD8 T-cell tumor infiltration. In B16-OVA syngeneic models, monotherapy and its combination with an anti-PD-1 antibody achieved robust tumor growth suppression, outperforming AC484, with no observable systemic toxicity. Collectively, represents a preclinical candidate with validated efficacy and safety for developing novel antimelanoma therapeutics.

PubMed: 41047545
DOI: 10.1021/acs.jmedchem.5c02300

Experimental method

X-RAY DIFFRACTION (1.95 Å)