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 NP19 inhibited the human PD-1/PD-L1 interaction with IC50 values of 12.5 nM in homogeneous time-resolved fluorescence
(HTRF) binding assays. In addition, NP19 dose-dependently
elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1
and CD3 T cells. Furthermore, NP19 displayed significant in vivo 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 NP19 activated the immune microenvironment in the
tumor, which may contribute to its antitumor effects. This work shows NP19 is a promising lead compound for further development
as a new generation of small molecule inhibitors targeting the PD-1/PD-L1
pathway.