Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
College of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
Bioorg Med Chem. 2021 Sep 15;46:116370. doi: 10.1016/j.bmc.2021.116370. Epub 2021 Aug 18.
Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by small-molecule inhibitors is emerging cancer immunotherapy. A series of novel 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for their activities in vitro and vivo to find potent inhibitors of the PD-1/PD-L1 interaction. Among them, compoundⅡ-14exhibited outstanding biochemical activity, with an ICof 0.0380 μM. Importantly, compound II-14, with a TGI value of 35.74 %, had more potent efficacy in a mouse tumor model compared to that in the control group. Surprisingly, when compound II-14 combined with 5-FU in a mouse tumor model having a TGI value of 64.59 %, which showed potential anti-tumor synergistic effects. Furthermore, immunohistochemistry analysis demonstrated thatcompound II-14 activated the immune microenvironment by promoting the infiltration of CD4 T cells into tumor tissues. These results indicate that compound II-14 is a promising lead compound for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.
小分子抑制剂抑制程序性细胞死亡-1（PD-1）/程序性细胞死亡配体 1（PD-L1）相互作用正在成为癌症免疫疗法。设计、合成了一系列新型 1,3,4-噁二唑衍生物，并对其体外和体内活性进行了评价，以寻找 PD-1/PD-L1 相互作用的强效抑制剂。其中，化合物Ⅱ-14 表现出优异的生化活性，IC₅₀值为 0.0380 μM。重要的是，与对照组相比，化合物Ⅱ-14 在小鼠肿瘤模型中具有更高的疗效，其肿瘤生长抑制（TGI）值为 35.74%。令人惊讶的是，当化合物Ⅱ-14 与 5-FU 在 TGI 值为 64.59%的小鼠肿瘤模型中联合使用时，表现出潜在的抗肿瘤协同作用。此外，免疫组织化学分析表明，化合物Ⅱ-14 通过促进 CD4 T 细胞浸润肿瘤组织来激活免疫微环境。这些结果表明，化合物Ⅱ-14 是进一步开发用于癌症治疗的小分子 PD-1/PD-L1 抑制剂的有前途的先导化合物。
