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

Bioorg Med Chem Lett. 2021 Nov 15:52:128403. doi: 10.1016/j.bmcl.2021.128403. Epub 2021 Oct 2.

Abstract

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.

Keywords: Antitumor; Immunotherapy; PD-1/PD-L1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Immune Checkpoint Inhibitors / chemical synthesis
  • Immune Checkpoint Inhibitors / chemistry
  • Immune Checkpoint Inhibitors / pharmacology*
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Structure-Activity Relationship

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Immune Checkpoint Inhibitors
  • Isoxazoles
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor