Synthesis and pharmacological evaluation of novel resorcinol biphenyl ether analogs as small molecule inhibitors of PD-1/PD-L1 with benign toxicity profiles for cancer treatment.

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) pathway is one of the most actively pursued targets in cancer immunotherapy. In a continuation of our research interest in this pathway, we synthesized and evaluated the pharmacological activities of a series of resorcinol biphenyl ether analogs as small molecule PD-1/PD-L1 inhibitors for cancer treatment. Among the 27 newly synthesized compounds, CH1 was found to have the highest inhibitory effect against PD-1/PDL-1 with an IC value of 56.58 nM in the HTRF (homogenous time-resolved fluorescence) assay. In addition, CH1 dose-dependently promoted HepG2 cell death in a co-culture model of HepG2/hPD-L1 and Jurkat T cells. Furthermore, molecular modeling study indicated that CH1 binds with high affinity to the binding interface of PD-L1. Moreover, CH1 effectively inhibited tumor growth (TGI of 76.4% at 90 mg/kg) in an immune checkpoint humanized mouse model with no obvious toxicity. Finally, CH1 did not cause in vivo cardiotoxicity and bone marrow suppression (myelosuppression) to BALB/c mice. Taken together, these results suggest that CH1 deserves further investigation as a potent and safe PD-1/PDL-1 inhibitor for cancer treatment.