Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage

Blockade of immune
checkpoint PD-1/PD-L1 has been a promising anticancer
strategy; however, clinically available PD-1/PD-L1 small-molecule
inhibitors are lacking. In view of the high potency of compound 2 (BMS-1002), structural fine tuning of the methoxy linkage
together with diverse modification in the solvent interaction region
was conducted. A series of novel derivatives featuring a difluoromethyleneoxy
linkage were designed. Compound 43 was identified as
the most promising PD-1/PD-L1 inhibitor with an IC50 value
of 10.2 nM in the HTRF assay. This compound is capable of promoting
CD8+ T cell activation through inhibiting PD-1/PD-L1 cellular
signaling. Moreover, in the Hepa1-6 syngeneic mouse model, administration
of compound 43 at 1 mg/kg dosage promoted CD8+ T cell activation and delayed the tumor growth with good tolerance.
Notably, the tumor in one mouse of the compound 43-treated
group was completely regressed. These results indicate that compound 43 is a promising candidate worthy of further investigation.