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

Abstract

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. <b>P39</b> was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC₅₀ = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that <b>P39</b> induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, <b>P39</b> exhibited a favorable safety profile with a LD₅₀ > 5000 mg/kg and showed significant <i>in vivo</i> antitumor activity through promoting CD8⁺ T cell activation. All these data suggest that <b>P39</b> 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.