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.