This new review article, written primarily by PhD students Elle Watson and Jack Hutchinson, summarises the progress in designing and developing small-molecule inhibitors of DNA-dependent protein kinase (DNA-PK), a key enzyme involved in repairing DNA double-strand breaks through the non-homologous end joining (NHEJ) pathway. Because DNA-PK is often overexpressed in cancers and contributes to resistance against chemotherapy and radiotherapy, it has emerged as an important target for anticancer drug development.

The review describes the evolution of DNA-PK inhibitors from early, non-selective compounds to highly potent and selective clinical candidates. It discusses medicinal chemistry strategies used to improve potency, selectivity, pharmacokinetic properties and safety, highlighting important structure-activity relationships (SAR) and synthetic approaches.

The paper also reviews the current status of DNA-PK inhibitors in clinical trials, their use in combination with radiotherapy, chemotherapy and PARP inhibitors and the remaining challenges related to efficacy, toxicity and resistance.