2. Academic Validation
  3. Novel PD-L1/VISTA Dual Inhibitor as Potential Immunotherapy Agents

Novel PD-L1/VISTA Dual Inhibitor as Potential Immunotherapy Agents

  • J Med Chem. 2025 Jan 9;68(1):156-173. doi: 10.1021/acs.jmedchem.4c01640.
Chengliang Sun 1 2 3,  Yao Cheng 1 4,  Jingwen Dong 5,  Lingrong Hu 1 2 3,  Yu Zhang 1 4 6,  Hao Shen 1 2 3,  Guoyu Zhang 1 2 3,  Binjian Jiang 1 2 3,  Salouoi Adam Youssouf 1 2 3,  Wenjian Min 1 2 3,  Yuxia Shen 1 2 3,  Liping Wang 1 2 3,  Hongbin Deng 5,  Yibei Xiao 1 4 7,  Peng Yang 1 2 3
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 Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 6 School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China.
  • 7 Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
PMID: 39731560 DOI: 10.1021/acs.jmedchem.4c01640
Abstract

Inhibiting the activity of Immune Checkpoint Proteins to reignite the antitumor activity of immune cells has emerged as a pivotal strategy. PD-L1 and VISTA, as critical proteins governing immune regulation, are concurrently upregulated under conditions such as hypoxia. Through a rational drug design process, P17, a dual-target inhibitor for PD-L1 and VISTA is identified. This inhibitor blocks the signaling pathways of both PD-L1 and VISTA at the protein and cellular levels, thereby reactivating the antitumor function of T cells. P17 displays encouraging attributes in terms of druggability and safety assessments. Notably, P17 demonstrates superior antitumor efficacy compared to single-target inhibitors at equivalent doses in in vivo experiments. More crucially, P17 significantly enhances the infiltration of immune cells. This study not only validates the effectiveness of a dual-target inhibitor strategy against PD-L1 and VISTA, but also identifies P17 as a promising candidate molecule with significant therapeutic potential.

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