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Publication Abstract from PubMed

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 (IC(50) = 7.05 nM) with high safety (hERG IC(50) > 40 muM) and excellent liver metabolic stability (T(1/2) = 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-gamma 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.

Targeting Protein Tyrosine Phosphatase Nonreceptor Type 2 with a Novel Inhibitor for the Treatment of Melanoma.,Kuang W, Li Q, Wang W, Wang D, Tong C, Song M, Han K, Liu J, Chen A, Chen Y, Wang L, Hao H, Wang X, Xiao Y, Yang P J Med Chem. 2025 Nov 27;68(22):24649-24671. doi: 10.1021/acs.jmedchem.5c02622. , Epub 2025 Nov 8. PMID:41204903^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.