9vrr

Crystal structure of human PTPN2 with inhibitor WS3

spinqualitylabelsall models 9vrr, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9vrr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.95Å Ligands: A1ETL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PTN2_HUMAN Publication Abstract from PubMed 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 WS35 horizontal line a potent dual PTPN2/1 inhibitor exhibiting exceptional enzymatic activity (PTPN2 IC(50) = 5.8 nM, PTPN1 IC(50) = 12.8 nM), favorable safety profiles, and enhanced oral bioavailability (F = 7.1%). Mechanistic studies demonstrate that WS35 modulates the IFNgamma-JAK-STAT signaling axis, significantly augmenting CD8(+) T-cell tumor infiltration. In B16-OVA syngeneic models, WS35 monotherapy and its combination with an anti-PD-1 antibody achieved robust tumor growth suppression, outperforming AC484, with no observable systemic toxicity. Collectively, WS35 represents a preclinical candidate with validated efficacy and safety for developing novel antimelanoma therapeutics. Development of Novel PTPN2/1 Inhibitors for the Treatment of Melanoma.,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 J Med Chem. 2025 Oct 23;68(20):21917-21938. doi: 10.1021/acs.jmedchem.5c02300. , Epub 2025 Oct 5. PMID:41047545 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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