2. Academic Validation
  3. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

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

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. elaine.cadogan@astrazeneca.com.
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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