Development of Novel PTPN2/1 Inhibitors for the Treatment of Melanoma.

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─a potent dual PTPN2/1 inhibitor exhibiting exceptional enzymatic activity (PTPN2 IC50 = 5.8 nM, PTPN1 IC50 = 12.8 nM), favorable safety profiles, and enhanced oral bioavailability (F = 7.1%). Mechanistic studies demonstrate that WS35 modulates the IFNγ-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.