Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy.Despite the inherent advantages of small-molecule inhibitors over antibodies,the discovery of small-molecule inhibitors has fallen behind that of antibody drugs.Based on docking studies between small molecule inhibitor and PD-L1 protein,changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein,which was not reported before.A series of novel phthalimide derivatives from structure-based rational design was synthesized.P39 was identified as the best inhibitor with promising activity,which not only inhibited PD-1/PD-L1 interaction(IC_(50)=8.9 nmol/L),but also enhanced killing efficacy of immune cells on cancer cells.Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins,thereby blocking the binding of PD-1/PD-L1.Moreover,P39 exhibited a favorable safety profile with a LD_(50)>5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8^(+)T cell activation.All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.