Identification of the FDA-Approved Drug Pyrvinium as a Small-Molecule Inhibitor of the PD-1/PD-L1 Interaction

ChemMedChem. 2021 Sep 16;16(18):2769-2774. doi: 10.1002/cmdc.202100264. Epub 2021 Jun 29.


Immune checkpoint blockade involving inhibition of the PD-1/PD-L1 interaction has provided unprecedented clinical benefits in treating a variety of tumors. To date, a total of six antibodies that bind to either PD-1 or PD-L1 protein and in turn inhibit the PD-1/PD-L1 interaction have received clinical approvals. Despite being highly effective, these expensive large biotherapeutics possess several inherent pharmacokinetic limitations that can be successfully overcome through the use of low-molecular-weight inhibitors. One such promising approach involves small-molecule induced dimerization and sequestration of PD-L1, leading to effective PD-1/PD-L1 inhibition. Herein, we present the discovery of such potential bioactive PD-L1 dimerizers through a structure- and ligand-based screening of a focused library of approved and investigational drugs worldwide. Pyrvinium, an FDA-approved anthelmintic drug, showed the highest activity in our study with IC50 value of ∼29.66 μM. It is noteworthy that Pyrvinium, being an approved drug, may prove especially suitable as a good starting point for further medicinal chemistry efforts, leading to design and development of even more potent structural analogs as selective PD-1/PD-L1 inhibitors. Furthermore, the adopted integrated virtual screening protocol may prove useful in screening other larger databases of lead- and drug-like molecules for hit identification in the domain of small-molecule PD-1/PD-L1 inhibitors.

Keywords: Cancer; Immunology; PD-1/PD-L1; Pyrvinium; Small-molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Pyrvinium Compounds / chemical synthesis
  • Pyrvinium Compounds / chemistry
  • Pyrvinium Compounds / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • United States
  • United States Food and Drug Administration


  • B7-H1 Antigen
  • CD274 protein, human
  • Ligands
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Pyrvinium Compounds
  • Small Molecule Libraries
  • pyrvinium