Liu Jin, Cheng Yao, Yuan Lin, Liu Ting, Ruan Yong, Ren Yichang, Li Ling, Jiang Sheng, Xiao Yibei, Chen Jianjun
School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
J Med Chem. 2023 Sep 28;66(18):13172-13188. doi: 10.1021/acs.jmedchem.3c01141. Epub 2023 Sep 6.
Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as small-molecule PD-1/PD-L1 inhibitors. Among them, compound exhibited the most potent PD-L1 inhibitory activity with an IC of 16.7 nM, 3.2-fold better than the lead (IC = 53.6 nM). The X-ray crystal structure of in complex with PD-L1 was solved at a resolution of 2.6 Å, which further confirmed the high binding affinity of to PD-L1. In the HepG2/Jurkat T cell co-culture model, effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, showed excellent antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, represents the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.
目前的小分子PD-1/PD-L1抑制剂主要基于芳基甲胺/联苯核心骨架。在此，我们首次设计了一系列非芳基甲胺类似物（恶二唑硫醚衍生物）作为小分子PD-1/PD-L1抑制剂。其中，化合物表现出最有效的PD-L1抑制活性，IC50为16.7 nM，比先导化合物（IC50 = 53.6 nM）高3.2倍。化合物与PD-L1复合物的X射线晶体结构以2.6 Å的分辨率解析，这进一步证实了化合物与PD-L1的高结合亲和力。在HepG2/Jurkat T细胞共培养模型中，化合物通过恢复T细胞的免疫功能有效促进了HepG2细胞死亡。此外，化合物在B16-F10肿瘤模型中通过调节PD-L1表现出优异的抗肿瘤疗效（30 mg/kg时TGI = 88.6%）和良好的毒性特征。总之，化合物代表了首个值得进一步研究的基于非芳基甲胺的小分子PD-1/PD-L1抑制剂。
