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 <b>K-38</b>, a potent PTPN2 inhibitor (IC₅₀ = 7.05 nM) with high safety (hERG IC₅₀ > 40 μM) and excellent liver metabolic stability (<i>T</i>_1/2 = 408 min). Compound <b>K-38</b> also showed improved oral bioavailability (<i>F</i> = 10.46%) over <b>AC-484</b> (<i>F</i> = 1.40%) (Zheng <i>European Journal of Medicinal Chemistry</i> 2024, 270, 116390, ). In vivo, compound <b>K-38</b> significantly suppressed melanoma growth, especially when combined with anti-PD-1 therapy, outperforming <b>AC-484</b>. It enhanced lymphocyte infiltration into tumors and modulated IFN-γ signaling pathways. These findings indicate that compound <b>K-38</b> is a potent small molecule inhibitor of PTPN2, laying the groundwork for the future development of PTPN2-targeted therapeutics.