Discovery of [1,2,4]Triazolo[4,3- a]pyridines as Potent Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

J Med Chem. 2019 May 9;62(9):4703-4715. doi: 10.1021/acs.jmedchem.9b00312. Epub 2019 Apr 19.


Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction using small-molecule inhibitors is an emerging immunotherapeutic approach. A novel series of [1,2,4]triazolo[4,3- a]pyridines were designed and found to be potent inhibitors of the PD-1/PD-L1 interaction. Among them, compound A22 exhibited the most potent activity, as assessed by homogenous time-resolved fluorescence assay, with an IC50 of 92.3 nM. Furthermore, A22 dose-dependent elevated interferon-γ production in a co-culture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. We concluded that A22 is a promising lead compound for the development of inhibitors of the PD-1/PD-L1 interaction. In addition, we explored the structure-activity relationships of the newly synthesized [1,2,4]triazolo[4,3- a]pyridines and demonstrated that a ring fusion strategy can be employed for designing analogues of the Bristol-Myers Squibb chemical series. These studies pave the way for future drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / chemistry
  • B7-H1 Antigen / metabolism*
  • Binding Sites
  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Interferon-gamma / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Programmed Cell Death 1 Receptor / chemistry
  • Programmed Cell Death 1 Receptor / metabolism*
  • Protein Binding / drug effects*
  • Pyridines / chemical synthesis
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / metabolism
  • Triazoles / pharmacology*


  • B7-H1 Antigen
  • CD274 protein, human
  • IFNG protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Pyridines
  • Triazoles
  • Interferon-gamma