2. Academic Validation
  3. Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

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

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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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157937
    VISTA Inhibitor