Discovery of Novel Resorcinol Dibenzyl Ethers Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction as Potential Anticancer Agents.

Novel small molecule compounds based on various scaffolds including chalcone, flavonoid, and resorcinol dibenzyl ether were designed and tested for their inhibitory activity against the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) pathway. Among them, compound inhibited the human PD-1/PD-L1 interaction with IC values of 12.5 nM in homogeneous time-resolved fluorescence (HTRF) binding assays. In addition, dose-dependently elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, displayed significant antitumor efficacy in two different mouse models of cancer (a melanoma B16-F10 tumor model and an H22 hepatoma tumor model). Moreover, H&E staining and flow cytometry data suggested that activated the immune microenvironment in the tumor, which may contribute to its antitumor effects. This work shows is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the PD-1/PD-L1 pathway.