Novel PD-L1/VISTA Dual Inhibitor as Potential Immunotherapy Agents
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, <b>P17</b>, 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. <b>P17</b> displays encouraging attributes in terms of druggability and safety assessments. Notably, <b>P17</b> demonstrates superior antitumor efficacy compared to single-target inhibitors at equivalent doses in in vivo experiments. More crucially, <b>P17</b> 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 <b>P17</b> as a promising candidate molecule with significant therapeutic potential.
Authors
- Wenjian Min (ORCID: https://orcid.org/0000-0002-0519-0654)
- Lingrong Hu
- Jingwen Dong (ORCID: https://orcid.org/0000-0003-0259-8125)
- Peng Yang (ORCID: https://orcid.org/0000-0002-2613-941X)
- Liping Wang (ORCID: https://orcid.org/0000-0001-9173-0882)
- Salouoi Adam Youssouf
- Yibei Xiao (ORCID: https://orcid.org/0000-0003-4716-5526)
- Hao Shen (ORCID: https://orcid.org/0000-0002-8698-5079)
- Yu Zhang (ORCID: https://orcid.org/0000-0002-2172-5540)
- Binjian Jiang
- Yao Cheng (ORCID: https://orcid.org/0000-0001-5258-0762)
- Guoyu Zhang
- Hongbin Deng (ORCID: https://orcid.org/0000-0002-4398-8819)
- Chengliang Sun (ORCID: https://orcid.org/0000-0002-8428-0091)
- Yuxia Shen
Institutions
- China Pharmaceutical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Medicina (PL)
- Institute of Medicinal Plant Development (CN)
- State Key Laboratory of Natural Medicine
- University of Hong Kong (HK)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01640
- Citations
- 5
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities