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 (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 was identified as the most promising PD-1/PD-L1 inhibitor with an IC 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 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 -treated group was completely regressed. These results indicate that compound is a promising candidate worthy of further investigation.