Novel Benzimidazoles as Potent Small-Molecule Inhibitors and Degraders of V-Domain Ig Suppressor of T-Cell Activation (VISTA).
Novel Benzimidazoles as Potent Small-Molecule Inhibitors and Degraders of V-Domain Ig Suppressor of T-Cell Activation (VISTA).
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DOI：
10.1021/acs.jmedchem.3c00484
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发表时间：
2023-08
影响因子：
7.3
通讯作者：
Tianyu Wang;Kaizhen Wang;Yu Zhang;Kuojun Zhang;S. Cai;Sheng Jiang;Yibei Xiao;Xiangyu Zhang
中科院分区：
文献类型：
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作者：
Tianyu Wang;Kaizhen Wang;Yu Zhang;Kuojun Zhang;S. Cai;Sheng Jiang;Yibei Xiao;Xiangyu Zhang
T细胞活化的V域IG抑制因子（VISTA）是一种很有前途的负性免疫检查点，在调节幼稚T淋巴细胞的静止中起着关键作用。然而，大多数患者并没有经历来自当前免疫检查点抑制剂的持久疾病控制，并且有必要发现靶向新型免疫检查点的抑制剂。在此，我们报告了我们的发现和优化的苯并咪唑作为VISTA的双功能抑制剂。化合物1被鉴定为靶向VISTA的双功能抑制剂，其显示出对VISTA的良好结合亲和力并通过自噬机制诱导HepG2细胞中的VISTA降解。化合物1有效地挽救VISTA介导的免疫抑制并增强免疫细胞的抗肿瘤活性。1在体内激活抗肿瘤免疫并显著抑制CT26小鼠模型中的肿瘤生长。我们的结果表明，化合物1是一种有前途的VISTA抑制剂和降解剂，并通过VISTA降解为癌症免疫治疗提供了新的方法。
The V-domain Ig suppressor of T-cell activation (VISTA) is a promising negative immune checkpoint and plays a critical role in the regulation of the quiescence of naïve T lymphocytes. Most patients however do not experience durable disease control from current immune checkpoint inhibitors and discovery of inhibitors targeting novel immune checkpoints is necessary. Herein, we report our discovery and optimization of benzimidazoles as the bifunctional inhibitors of VISTA. Compound 1 is identified as a bifunctional inhibitor targeting VISTA, which shows good binding affinity to VISTA and induces VISTA degradation in HepG2 cells through an autophagic mechanism. Compound 1 rescues VISTA-mediated immunosuppression effectively and enhances antitumor activity of immune cells. 1 activates the antitumor immunity in vivo and suppresses tumor growth in a CT26 mouse model significantly. Our results show that compound 1 is a promising VISTA inhibitor and degrader and offers novel approach for cancer immunotherapy through VISTA degradation.