Development of DNA-PK-targeting PROTACs to maximise DNA-PK blockage in advanced prostate cancer

Prostate cancer accounts for 375,000 deaths per year worldwide. Targeting the androgen receptor (AR) using hormone therapy is the mainstay treatment for advanced prostate cancer. Unfortunately, not all patients show durable responses; with many becoming resistant to radiotherapy or acquiring mechanisms that overcome AR blockade. Hence, there is an urgent need to provide more effective and durable treatments for metastatic disease. In advanced prostate cancer, DNA-dependent protein kinase (DNA-PK) expression is elevated and correlates with metastatic spread. The project has two main objectives: 1) to develop DNA-PKcs PROTACs to destabilise DNA-PKcs in prostate cancer; 2) to demonstrate unequivocal levels of DNA-PKcs inhibition in a range of in vitro assays across a range of prostate cancer cell lines and provide the means to evaluate DNA-PK degradation as a potential treatment in advanced prostate cancer.