AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

Nat Commun. 2019 Nov 7;10(1):5065. doi: 10.1038/s41467-019-12836-9.


DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects*
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • Doxorubicin / analogs & derivatives
  • Doxorubicin / pharmacology
  • Drug Synergism*
  • Genomic Instability / drug effects
  • Humans
  • Lung Neoplasms
  • Mice
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Polyethylene Glycols / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Purines / pharmacology*
  • Pyrans / pharmacology*
  • Radiation Tolerance / drug effects*
  • Radiotherapy
  • Triazoles / pharmacology*
  • Xenograft Model Antitumor Assays


  • AZD7648
  • Antibiotics, Antineoplastic
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protein Kinase Inhibitors
  • Purines
  • Pyrans
  • Triazoles
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Doxorubicin
  • DNA-Activated Protein Kinase
  • olaparib