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
  • 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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