Insights into non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction: Development and perspective

Bioorg Med Chem. 2021 Mar 1:33:116038. doi: 10.1016/j.bmc.2021.116038. Epub 2021 Jan 22.

Abstract

The development of immune checkpoint inhibitors has become a research hotspot in cancer immunotherapy in recent years. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs), such as pembrolizumab and nivolumab have been approved for treating different types of cancer. Many peptides, peptidomimetics and non-peptide small-molecule inhibitors targeting the PD-1/PD-L1 axis have been published so far. In comparison with mAbs, small-molecule inhibitors have the potential to overcome inherent shortcomings of mAbs, such as poor oral bioavailability, low tumor penetration, and high manufacturing costs. In this article, we mainly review non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction, their cocrystal structures, docking studies, and biological activities are also included to guide future study. In addition, we propose several strategies for designing more effective small-molecule modulators of the PD-1/PD-L1 pathway.

Keywords: Cancer immunotherapy; Non-peptide small-molecule inhibitors; Rational drug design; The PD-1/PD-L1 blockade.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / chemistry
  • Drug Development*
  • Humans
  • Immune Checkpoint Inhibitors / chemistry
  • Immune Checkpoint Inhibitors / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / chemistry
  • Protein Binding / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

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