Back to Search
Start Over
Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors
- Source :
- Journal of Medicinal Chemistry; March 2024, Vol. 67 Issue: 5 p3590-3605, 16p
- Publication Year :
- 2024
-
Abstract
- VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1that binds to VISTA protein with high affinity and optimized its structure. A4was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KDvalue of 0.49 ± 0.20 μM. In vitro, A4significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Volume :
- 67
- Issue :
- 5
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs65591651
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.3c02039