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

  • J Med Chem. 2025 Nov 27;68(22):24649-24671. doi: 10.1021/acs.jmedchem.5c02622.
Wenbin Kuang  1  2 ,  Qiannan Li  1  3 ,  Wenmu Wang  1  2 ,  Dawei Wang  1  2 ,  Chen Tong  1  3 ,  Mingge Song  1  2 ,  Kailin Han  4 ,  Jianing Liu  1  2 ,  Anyan Chen  1  2 ,  Ya Chen  5 ,  Liping Wang  1  2 ,  Haiping Hao  1  2  5 ,  Xiao Wang  1  2  5 ,  Yibei Xiao  1  5  3 ,  Peng Yang  1  2  5
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Department of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 4. Tasly Academy, Tasly Pharmaceutical Group Co., Ltd., Tianjin 300410, China.
  • 5. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41204903 DOI: 10.1021/acs.jmedchem.5c02622
Abstract

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.

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