Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

  • J Med Chem. 2024 Feb 27. doi: 10.1021/acs.jmedchem.3c02039.
Chengliang Sun  1  2  3 ,  Yuling He  1  4 ,  Gefei Wang  1  2  3 ,  Guoyu Zhang  1  2  3 ,  Yu Zhang  1  4 ,  Hao Shen  1  2  3 ,  Lingrong Hu  1  2  3 ,  Yanze Sun  1  2  3 ,  Binjian Jiang  1  2  3 ,  Xiao Wang  1  2  3 ,  Kai Yuan  1  2  3 ,  Wenjian Min  1  2  3 ,  Liping Wang  1  2  3 ,  Haopeng Sun  2 ,  Yibei Xiao  1  4  5 ,  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. Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
PMID: 38412237 DOI: 10.1021/acs.jmedchem.3c02039
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 A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 μM. In vitro, A4 significantly 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, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against Cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

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