School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Innovation Department of the Research Institute, Nanjing Chia-Tai Tianqing Pharmaceutical Co., Ltd., Nanjing 210046, China.
J Med Chem. 2024 Oct 24;67(20):18526-18548. doi: 10.1021/acs.jmedchem.4c01899. Epub 2024 Oct 10.
The blockers of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway have achieved great clinical success. However, the limited efficacy and low tumor response rate of anti-PD-1/PD-L1 monotherapy limit the clinical application of PD-1/PD-L1 inhibitors. V-domain immunoglobulin suppressor of T-cell activation (VISTA), a novel checkpoint regulator, exhibits potential synergy with PD-1/PD-L1 in enhancing antitumor immunity. Herein, we report the discovery of benzo[]oxazole as novel dual small-molecule inhibitors targeting PD-1/PD-L1 and VISTA with high PD-1/PD-L1 inhibitory activity and VISTA binding affinity. rescues the immunosuppression of T-cells mediated by PD-L1 and VISTA and activates antitumor immunity effectively. Moreover, could induce degradation of PD-L1 and VISTA in tumor cell. Furthermore, displays significant antitumor efficacy in a CT26 mouse model. Our results discover as a promising dual PD-1/PD-L1 and VISTA inhibitor, providing a novel therapeutic strategy to overcome the limitations of current anti-PD-1/PD-L1 therapy.
程序性细胞死亡蛋白-1（PD-1）/程序性细胞死亡配体 1（PD-L1）通路抑制剂已取得巨大的临床成功。然而，抗 PD-1/PD-L1 单药治疗的疗效有限且肿瘤应答率低，限制了 PD-1/PD-L1 抑制剂的临床应用。T 细胞激活的 V 结构域免疫球蛋白抑制物（VISTA）是一种新型检查点调节剂，与 PD-1/PD-L1 联合应用具有增强抗肿瘤免疫的潜力。在此，我们报道了苯并[o]恶唑作为新型双重小分子抑制剂的发现，该抑制剂可同时靶向 PD-1/PD-L1 和 VISTA，具有高 PD-1/PD-L1 抑制活性和 VISTA 结合亲和力。 可挽救 PD-L1 和 VISTA 介导的 T 细胞免疫抑制，并有效激活抗肿瘤免疫。此外， 可诱导肿瘤细胞中 PD-L1 和 VISTA 的降解。此外， 在 CT26 小鼠模型中显示出显著的抗肿瘤疗效。我们的研究结果发现 是一种有前途的双重 PD-1/PD-L1 和 VISTA 抑制剂，为克服当前抗 PD-1/PD-L1 治疗的局限性提供了一种新的治疗策略。
