State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem. 2024 Mar 14;67(5):3590-3605. doi: 10.1021/acs.jmedchem.3c02039. Epub 2024 Feb 27.
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 that binds to VISTA protein with high affinity and optimized its structure. was then obtained, which exhibited the strongest binding ability to VISTA protein, with a value of 0.49 ± 0.20 μM. , 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. , displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.
VISTA（T 细胞激活的免疫球蛋白域抑制剂）是一种新型免疫检查点蛋白，是癌症免疫治疗的一个有前途的靶点。在这里，我们报告了一系列基于甲氧基嘧啶的 VISTA 小分子抑制剂的设计、合成和评估，这些抑制剂具有很强的抗肿瘤活性。通过分子对接和微量热泳动（MST）实验，我们确定了一个与 VISTA 蛋白具有高亲和力的先导化合物 ，并对其结构进行了优化。然后得到了 ，它与 VISTA 蛋白的结合能力最强， 值为 0.49±0.20 μM。 ，显著激活外周血单核细胞（PBMCs），诱导 IFN-γ 等细胞因子的释放，并增强 PBMCs 对肿瘤细胞的细胞毒性。 ，显示出很强的抗肿瘤活性，并与 PD-L1 抗体协同作用，增强对癌症的治疗效果。这些结果表明，化合物 是一种有效的 VISTA 小分子抑制剂，为未来开发 VISTA 靶向药物提供了依据。
