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.