Development of the Inhibitors that Target the PD-1/PD-L1 Interaction-A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

Molecules. 2019 May 30;24(11):2071. doi: 10.3390/molecules24112071.

Abstract

Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.

Keywords: PD-1/PD-L1 pathway; cancer immunotherapy; cocrystal structures; lead optimization; peptide-based and small synthetic molecule inhibitors; rational drug design; scaffold hopping; structure-activity relationship.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents, Immunological / chemistry
  • Antineoplastic Agents, Immunological / pharmacology*
  • B7-H1 Antigen / metabolism*
  • Drug Development* / methods
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Programmed Cell Death 1 Receptor / metabolism*
  • Protein Binding / drug effects
  • Quantitative Structure-Activity Relationship
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • Peptides
  • Programmed Cell Death 1 Receptor