2. Academic Validation
  3. Development of Novel PTPN2/1 Inhibitors for the Treatment of Melanoma

Development of Novel PTPN2/1 Inhibitors for the Treatment of Melanoma

  • J Med Chem. 2025 Oct 23;68(20):21917-21938. doi: 10.1021/acs.jmedchem.5c02300.
Dawei Wang 1 2,  Mingge Song 1 2,  Chen Tong 1 3,  Wenmu Wang 1 2,  Qiannan Li 1 3,  Jianing Liu 1 2,  Anyan Chen 1 2,  Ya Chen 4,  Liping Wang 1 2,  Haiping Hao 1 4 3,  Xiao Wang 1 2 4,  Kailin Han 5,  Yibei Xiao 1 3,  Wenbin Kuang 1 2,  Peng Yang 1 2 4
Affiliations

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 Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
  • 5 Tasly Academy, Tasly Pharmaceutical Group Co., Ltd., Tianjin 300410, China.
PMID: 41047545 DOI: 10.1021/acs.jmedchem.5c02300
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z