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Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation

Elle Watson1, Jack R R Hutchinson1, Suzannah J Harnor1

  • 1Cancer Research Horizons Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Newcastle University Bedson Building Newcastle upon Tyne NE1 7RU UK celine.cano@newcastle.ac.uk.

RSC Medicinal Chemistry
|June 10, 2026
PubMed

Insights

DNA-dependent protein kinase (DNA-PK) inhibitors are crucial for cancer therapy. This review details the development of potent DNA-PK inhibitors, discussing their therapeutic potential and clinical challenges.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • DNA-dependent protein kinase (DNA-PK) regulates DNA double-strand break repair via non-homologous end joining (NHEJ).
  • Dysregulated DNA-PK activity correlates with cancer progression and resistance to therapies, identifying it as a key therapeutic target.

Purpose of the Study:

  • To provide a comprehensive overview of the discovery and optimization of DNA-dependent protein kinase (DNA-PK) inhibitors.
  • To highlight structure-activity relationships, synthetic routes, and pharmacological profiles of various DNA-PK inhibitor generations.

Main Methods:

  • Review of medicinal chemistry efforts in optimizing DNA-PK inhibitors.
  • Analysis of structure-activity relationships and synthetic strategies for inhibitor development.
  • Evaluation of pharmacological profiles and clinical progress of representative DNA-PK inhibitors.

Main Results:

  • Significant advancements have been made in developing potent, selective, and orally bioavailable DNA-PK inhibitors.
  • Key scaffolds and clinical candidates like AZD7648 and VX-984 have emerged.
  • Early-phase clinical trials are underway, with ongoing evaluation of tolerability and efficacy.

Conclusions:

  • DNA-PK inhibitors demonstrate significant therapeutic potential in cancer treatment.
  • Challenges remain in achieving optimal tolerability and efficacy, particularly in combination therapies.
  • This review offers a framework for future development of DNA-PK-targeted therapeutics.

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