Radiotherapy is a cornerstone modality in modern cancer treatment. DNA-dependent protein kinase (DNA-PK) plays a key role in repair of radiation-induced DNA damage. Existing DNA-PK inhibitors sensitise tumour cells to radiotherapy, but also cause off-target toxicity. We have recently discovered new, potent and selective inhibitors of DNA-PK. To further enhance the therapeutic window we will develop prodrugs that are only converted to active inhibitors in low oxygen (hypoxic) regions found inside most tumours. We will test the anticancer activity of our inhibitors and prodrugs in head and neck squamous cell carcinoma (HNSCC) cells, 3-dimensional tissue cultures and tumour models, in comparison with known DNA-PK inhibitors, to identify the best candidate for clinical development. Our long term objective is to support first-in-human clinical trials in NZ of a DNA-PK radiosensitiser for head and neck cancer.