Design, synthesis, and structure–activity relationship of PD-1/PD-L1 inhibitors with a benzo[d]isoxazole scaffold

Blocking the programmed cell death protein 1 (PD-1) and programmed death-ligand (PD-L1) interaction has emerged as one of the most promising treatments for cancer immunotherapy. A novel series of compounds bearing a benzo[d]isoxazole scaffold was developed as PD-1/PD-L1 inhibitors, among them, compound P20 exhibited the most potent inhibitory activity, with an IC50 value of 26.8 nM. The preliminary structure–activity relationship was also investigated. The docking analysis of compound P20 with the PD-L1 dimer complex (PDB ID: 5j89) indicated that compound P20 was bound to the PD-L1 dimer with high affinity. These results suggest that compound P20 is a promising lead compound for the development of inhibitors of the PD-1/PD-L1 interaction.