Design,Synthesis And Biological Activity Evaluation Of Small Molecule PD-1/PD-L1 Inhibitors Of Novel Resorcinol Dibenzyl Ether Analogues

Cancer(malignant tumor)has become a major threat to human health.As one of the many cancer treatment methods,immunotherapy has achieved great success.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/PD-L1 with an IC50 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/PD-L1 inhibitor for cancer treatment.