Targeting Protein Tyrosine Phosphatase Nonreceptor Type 2 with a Novel Inhibitor for the Treatment of Melanoma

Melanoma is a highly aggressive skin
cancer with strong metastatic
potential, posing significant clinical challenges. Currently, melanoma
treatment commonly includes chemotherapy and immunotherapy; nevertheless,
the treatment modalities have specific limitations. PTPN2 (protein
tyrosine phosphatase nonreceptor type 2) has emerged as a promising
therapeutic target. Through rational drug design, we identified compound K-38, a potent PTPN2 inhibitor (IC50 = 7.05 nM)
with high safety (hERG IC50 > 40 μM) and excellent
liver metabolic stability (T1/2 = 408
min). Compound K-38 also showed improved oral bioavailability
(F = 10.46%) over AC-484 (F = 1.40%) (Zheng European Journal of Medicinal
Chemistry 2024, 270, 116390, ). In vivo, compound K-38 significantly suppressed melanoma growth, especially when combined
with anti-PD-1 therapy, outperforming AC-484. It enhanced
lymphocyte infiltration into tumors and modulated IFN-γ signaling
pathways. These findings indicate that compound K-38 is
a potent small molecule inhibitor of PTPN2, laying the groundwork
for the future development of PTPN2-targeted therapeutics.