The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5- a]pyridin-6-yl)amino]-9-(tetrahydro-2 H-pyran-4-yl)-7,9-dihydro-8 H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor

J Med Chem. 2020 Apr 9;63(7):3461-3471. doi: 10.1021/acs.jmedchem.9b01684. Epub 2020 Jan 15.


DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-target activity in the protein kinome and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).

Publication types

  • News

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • Dogs
  • Drug Discovery
  • Humans
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • Purines / chemical synthesis
  • Purines / pharmacokinetics
  • Purines / therapeutic use*
  • Pyrans / chemical synthesis
  • Pyrans / pharmacokinetics
  • Pyrans / therapeutic use*
  • Rats
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / therapeutic use*
  • Xenograft Model Antitumor Assays


  • AZD7648
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Purines
  • Pyrans
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Triazoles
  • Class Ib Phosphatidylinositol 3-Kinase
  • DNA-Activated Protein Kinase

Associated data