First-in-class Selective IKKalpha Inhibitors for the Treatment of Castrate Resistant Prostate Cancer (CRPC) and Pancreatic Cancer

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Despite real progress being made in the treatment of many cancers, there are still significant issues to overcome, particularly for patients who have become resistant to treatment, or where the cancer has spread beyond the original tumour. This is particularly true of prostate cancer, which is the most common cancer in men in the UK. There are 36,000 new cases of prostate cancer diagnosed every year in the UK and this figure is predicted to double over the next 20 years.Whilst there are treatments available for early-stage prostate cancer (cancer that is still confined to the prostate cancer), some men become resistant to treatment and the cancer progresses and spreads (metastasizes). This type of prostate cancer is called castrate resistant prostate cancer (CRPC) and current treatments can only extend life expectancy by up to 9 months. New medicines to treat this disease are therefore urgently needed.We have discovered a new way to treat CRPC. We have shown that there are high levels of a protein called IKKalpha in the tumours of men who had shorter time to death. We and our Project Partners have also shown that this same protein is involved in the progression from early-stage prostate cancer to CRPC. We believe that a drug which stops this protein from functioning will prevent CRPC from developing and increase life expectancy by up to 3 years. Evidence is also emerging that this IKKalpha protein also plays a role in pancreatic cancer, which is currently incurable.We are the only group to have developed compounds that stop this protein from functioning, without also stopping closely-related proteins from functioning (and resulting in unwanted side-effects).We have also demonstrated that our compounds, when added to prostate cancer cell samples in a laboratory environment, slow their growth and cause them to die. However, these compounds require further development and are not yet suitable as medicines for CRPC. For example, they are broken down in the body too quickly to exert their effects in a patient and they are also not very water-soluble, which would make them difficult to administer. The aim of this project is to design compounds with better properties (a process called lead optimisation).We will then be able to determine whether our optimised compounds stop IKKalpha from functioning and stop cancers growing and spreading in mice, without adverse or toxic effects. This is essential to demonstrate before testing in humans.This project involves medicinal chemists, biologists, clinicians and technology transfer professionals working together as a team to achieve the goal of effective new medicines for patients with CRPC and pancreatic cancer.