AR-NTD Inhibitors as a Novel Treatment Modality for Castrate Resistant Prostate Cancer

One in eight UK men will get prostate cancer, which is the second most common cause of cancer related death in men, with 12,000 deaths/year in the UK. Worldwide, the incidence of prostate cancer is expected to more than double over the next 20 years. The androgen receptor is established as a key drug target in advanced and metastatic prostate cancer. 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 protein, the amino-terminal domain, which is essential for function. Such inhibitors will be effective against receptor variants that have lost the ability to bind hormone and antiandrogen drugs and point mutations that alter the receptor hormone-binding profile, changes that result in the development of therapy-resistant prostate cancer. The inherent challenge is that the amino-terminal domain is structurally disordered and therefore not amenable to structure-based drug design approaches used for orthosteric antagonists. We have identified a lead series of small molecule inhibitors of the androgen receptor amino terminal domain. Our lead series, represented by key exemplars JE115, MCH895, and MCH1091, demonstrate binding with the receptor amino-terminal domain, inhibition of receptor-dependent transactivation, and loss of cell viability. Taken as a whole, the chemical equity identified demonstrates robust target engagement, good potency and opportunity to tune the properties effecting absorption, distribution, metabolism and excretion in the body (pharmacokinetics). In the current project, the critical gap we aim to address is to demonstrate that an optimum balance of potency and in vivo pharmacokinetics in our lead series can be achieved, furnishing compounds with annotated in vitro activity in relevant cell models of hormone-sensitive and insensitive prostate cancer, combined with encouraging pharmacokinetic properties. This will allow the identification of successor compounds that may be taken forward for future validation in preclinical animal models using patient derived tumours. We will therefore undertake a focussed programme of medicinal chemistry combined with pharmacokinetic profiling and validation in a series of well characterised cell models of hormone-sensitive and -insensitive prostate cancer. Accordingly, the expected deliverables will be an advanced lead candidate small molecule inhibitor of the androgen receptor (amino-terminal domain), with demonstrated in vitro efficacy and target engagement, coupled with acceptable in vivo properties determining absorption and distribution (i.e. orally bioavailability) and metabolic stability. This will be a key stage which will position us to further profile of our assets in relevant pharmacodynamic studies and provide a basis for optimisation towards a pre-candidate quality molecule. Ultimately, if successful, the chief beneficiaries will be a new treatment option for men with therapy-resistant prostate cancer.