Identifying New Drugs for the Treatment of Castrate Resistant Prostate Cancer: Targeting the Achilles' Heel of the Androgen Receptor.

Prostate cancer is second most common cancer in men world wide, with an estimated 1.3 million new cases in 2018. Men with advanced prostate cancer are treated with hormone therapy, drugs that block the action of the androgen receptor. This protein is found inside prostate cells, binds the hormone testosterone and is a key driver of prostate cancer. Drugs which block the actions of testosterone are a mainstay for the treatment of metastatic disease. These drugs reduce the production of testosterone or switch off the activity of the androgen receptor. However, their effectiveness is blunted by the development of drug-resistance leading to 'castrate resistant' disease. While the androgen receptor remains important in advanced disease, there are currently no new targeted therapies available. We aim to develop novel small molecule inhibitors to switch off androgen receptor activity independent of the hormone-binding status. Our ambitious, but achievable aim will target a part of the receptor, essential for function, but not involved in hormone binding. The effectiveness and drug-like properties of candidate small molecule inhibitors which bind specifically to the receptor will be tested for their ability to neutralise the androgen receptor in laboratory models of prostate cancer. This approach has the advantage of targeting all known forms of the receptor, including those with alterations (mutations) associated with castrate resistant disease. This highly innovative approach to prostate cancer treatment, has the potential to significantly improve the outcome for men with advanced disease.

The androgen receptor is a key drug target in advanced and metastatic prostate cancer, a major cause of cancer-related death in men. However, tumour cells become resistant to antiandrogen drugs, while remaining dependent on the receptor for growth and survival. There is, therefore, a need for new drugs to switch-off receptor activity. Our strategy is to develop small molecule inhibitors that bind to a different part of the receptor, the amino-terminal domain (NTD), which is essential for function. Such inhibitors will be effective against receptor splice variants lacking the ligand-binding domain and point mutations that alter the receptor ligand-binding profile, changes that result in the development of castrate resistant prostate cancer. The NTD is intrinsically structurally disordered and therefore not amenable to structure-based drug design. We have screened three libraries of drug-like molecules and have identified novel candidate small molecule inhibitors of receptor function. Two of these hits have been further validated in secondary assays. As these compounds target the NTD they are likely to have novel mechanisms of action from current antiandrogens. We aim to determine and optimise the structure-activity relationships of our two lead chemotypes. We will prioritise one hit series for extensive in vitro/in vivo DMPK studies, and demonstrate efficacy of the most promising candidates against preclinical models of prostate cancers. Our candidate inhibitors will be bench-marked against existing antiandrogens (biclautamide and enzalutamide) and an experimental inhibitor (EPI-001).The outcome will be the optimisation of a 'lead candidate' inhibitor of the androgen receptor-NTD, that can be taken forward for preclinical and clinical studies. The project represents the critical steps towards new drug development, with the potential to improve current treatment modalities for men with advanced prostate cancer.

Our research will contribute fundamental new knowledge with a range of potential beneficiaries in the public and commercial sectors, as outlined below.

1. Contribution to the economic competitiveness of the UK by enhancing researcher skills in the areas of medicinal chemistry, drug development and molecular endocrinology. The researchers employed will gain project specific technical and transferable skills, including effective communication, team working and data management. The researchers will also take part in the supervision of masters and undergraduate students, providing a platform for improved inter-personal communication, troubleshooting and project management, necessary skills in both academia and other sectors. In the short term, the benefits will be increased efficiency and management of the research project and in the medium/long term will be instrumental in increasing the pool of highly skilled workers which will contribute to the economic competitiveness of the UK.

2. Health service provision and policy.
The project will generate fundamental research findings relevant to clinical management of hormone-dependent diseases and age-related chronic conditions. Specifically, the outcome of our research will be new, targeted, therapies for men with advanced prostate cancer, where the cancer has developed resistance to current drugs. More broadly, with increased life expectancy and the number of people over 65 in the UK expected to increase by 19.4 % by 2025 [Lancet] our findings may have wider implications by informing public health policy on strategies for treating men with advanced and metastatic disease. This is likely to have long term economic benefits by reducing health and societal costs by maintaining an active and healthy ageing population.

3. Industrial partnerships.
The androgen receptor is a well validated drug target for the treatment of a range of disorders in men and women. The importance of the androgen receptor has prompted pharma companies to develop a new range of compounds that may act as selective androgen receptor modulators. In the medium to long term the findings of our research have the potential to guide the development of selective agonists/antagonists for the androgen receptor by both SMEs and large pharma.

4. The wider public.
The impact on the wider public in the short to medium term will be raised awareness of scientific research and in particular the implications of androgens and the androgen receptor in health and well-being.