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 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 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, restored the T cell function, leading to increased IFN-γ secretion. Moreover, in a humanized mouse model, compound significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.