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Lookup NU author(s): Elle Watson, Jack Hutchinson, Dr Suzannah HarnorORCiD, Dr Luke GaughanORCiD, Dr Celine CanoORCiD
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This journal is © The Royal Society of Chemistry, 2026. DNA-dependent protein kinase (DNA-PK) is a central regulator of non-homologous end joining (NHEJ), the dominant pathway for DNA double-strand break repair in mammalian cells. Aberrant DNA-PK activity is frequently associated with tumour progression as well as chemo- and radio-resistance, positioning DNA-PK as an attractive therapeutic target in cancer. Over the past few years, extensive medicinal chemistry efforts have enabled the optimisation of small molecule inhibitors of DNA-PK, from early, non-selective chemical probes into highly potent, selective and orally bioavailable compounds. This review provides a comprehensive overview of the discovery and optimisation of DNA-PK inhibitors, highlighting key structure–activity relationships, synthetic strategies and pharmacological profiles across several inhibitor generations. Representative scaffolds, including chromen-4-one derivatives and next-generation clinical candidates such as AZD7648 and VX-984, are discussed. Finally, we summarise current clinical progress in early phase trials and remaining challenges, including achieving tolerability and efficacy when compounds are administered both as a single agent, or in combination. Taken together, this review highlights both the therapeutic potential of DNA-PK-targeting inhibition and the challenges encountered in clinical development, providing a framework to guide future strategies for DNA-PK-targeted therapeutics.
Author(s): Watson E, Hutchinson JRR, Harnor SJ, Gaughan L, Cano C
Publication type: Review
Publication status: Published
Journal: RSC Medicinal Chemistry
Year: 2026
Pages: Epub ahead of print
Online publication date: 08/06/2026
Acceptance date: 24/05/2026
ISSN (electronic): 2632-8682
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/d6md00119j
DOI: 10.1039/d6md00119j
