Yang Zichao, Yang Pan, Xu Jianwei, Yang Xixiang, Zhou Jiayi, He Haiqi, Li Ling, Ren Yichang, Chen Meirong, Xiao Yibei, Chen Jianjun
Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
State Key Laboratory of Natural Medicines and Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2025 Jun 26;68(12):12593-12614. doi: 10.1021/acs.jmedchem.5c00344. Epub 2025 Jun 16.
Current studies on PD-1/PD-L1 small-molecule inhibitors mainly focus on modifying the linker region between the biphenyl ring and amino acid side chains, or transforming the biphenyl ring into a benzodioxane structure. Herein, we designed and synthesized a series of compounds by introducing a tail at the terminal phenyl ring as small-molecule PD-1/PD-L1 inhibitors. Among them, compound exhibited the most potent PD-L1 inhibitory activity (IC = 24.4 nM). The X-ray crystal structure further confirmed the high binding affinity of to PD-L1 dimer. In the HepG2/Jurkat T cell coculture model, promoted HepG2 cell apoptosis dose-dependently. In addition, showed excellent antitumor efficacy (TGI = 92.1%) in a Hepa1-6 mouse tumor model and increased CD8 cells in tumor microenvironment. Importantly, possessed favorable pharmacokinetic properties with an oral bioavailability of 15.9%. Collectively, compound represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.
目前关于PD-1/PD-L1小分子抑制剂的研究主要集中在修饰联苯环与氨基酸侧链之间的连接区域，或将联苯环转化为苯并二恶烷结构。在此，我们通过在末端苯环引入一个尾巴设计并合成了一系列化合物作为小分子PD-1/PD-L1抑制剂。其中，化合物表现出最强的PD-L1抑制活性（IC = 24.4 nM）。X射线晶体结构进一步证实了其与PD-L1二聚体的高结合亲和力。在HepG2/Jurkat T细胞共培养模型中，化合物剂量依赖性地促进HepG2细胞凋亡。此外，化合物在Hepa1-6小鼠肿瘤模型中显示出优异的抗肿瘤疗效（TGI = 92.1%），并增加了肿瘤微环境中的CD8细胞。重要的是，化合物具有良好的药代动力学性质，口服生物利用度为15.9%。总体而言，化合物是一种有前景的PD-1/PD-L1抑制剂，作为潜在的抗癌药物值得进一步研究。
