Design, Synthesis, and Biological Evaluation of Linear Aliphatic Amine-Linked Triaryl Derivatives as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction with Promising Antitumor Effects In Vivo

A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 58 could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, 58 restored the T cell function, leading to increased IFN-γ secretion. Moreover, in a humanized mouse model, compound 58 significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that 58 is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.

本研究设计、合成了一系列以线性脂肪胺为连接基团的新型三芳基衍生物，并对其作为PD-1/PD-L1抑制剂开展了体内外评价。在该化学系列中，化合物58对人源PD-L1（hPD-L1）展现出最强的抑制活性与结合亲和力，其半最大抑制浓度（IC50）为12 nM，解离常数（KD）为16.2 pM，结合效力约为人源PD-1（hPD-1）的2000倍。化合物58可在细胞表面结合人源PD-L1，并竞争性阻断人源PD-1与PD-L1的相互作用。在T细胞功能实验中，化合物58可恢复T细胞功能，使干扰素γ（IFN-γ）的分泌水平升高。此外，在人源化小鼠模型中，化合物58可显著抑制肿瘤生长且无明显毒性，静脉注射后展现出适度的药代动力学（PK）特性。上述结果表明，化合物58是一种极具开发潜力的先导化合物，可用于后续开发针对癌症治疗的小分子PD-1/PD-L1抑制剂。