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.
Jacqueline H L Fok  1 ,  Antonio Ramos-Montoya  1 ,  Mercedes Vazquez-Chantada  2 ,  Paul W G Wijnhoven  1 ,  Valeria Follia  1 ,  Neil James  1 ,  Paul M Farrington  1 ,  Ankur Karmokar  1 ,  Sophie E Willis  3 ,  Jonathan Cairns  4 ,  Jenni Nikkilä  1 ,  David Beattie  5 ,  Gillian M Lamont  5 ,  M Raymond V Finlay  5 ,  Joanne Wilson  6 ,  Aaron Smith  6 ,  Lenka Oplustil O'Connor  3 ,  Stephanie Ling  2 ,  Stephen E Fawell  1 ,  Mark J O'Connor  1 ,  Simon J Hollingsworth  7 ,  Emma Dean  8 ,  Frederick W Goldberg  5 ,  Barry R Davies  1 ,  Elaine B Cadogan  9
Affiliations
  • 1. Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 2. Mechanistic Biology and Profiling, Discovery Sciences, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 3. Translational Science, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 4. Quantitative Biology, Discovery Science, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 5. Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 6. DMPK, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 7. Oncology Business Unit, AstraZeneca, Cambridge, UK.
  • 8. Oncology Translational Medicine Unit, Early Clinical Development, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 9. Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK. [email protected].
PMID: 31699977 DOI: 10.1038/s41467-019-12836-9
Abstract

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.

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