Grant: Proof of Principle - PA: Cancer Early Detection, Imaging/Trans Therapeutics

The Androgen Receptor (AR) plays a major role in the development and progression of prostate cancer. Modern anti-AR drugs almost exclusively target the site on the AR that binds androgens. Unfortunately, the effectiveness of this type of treatment is usually temporary due to progression of tumour cells to a castration-resistant state. Thus, there is a pressing need for finding new ways to inhibit AR activity. In the current proposal, we have used computer-aided techniques developed in-house for high throughput screening of AR activity to discover a completely unique class of AR inhibitors that act on a newly identified site on the AR (BF-3 site). After our preliminary in silico screen of 50 million compounds, ~200 potential BF-3 binding candidates were tested, with 17 showing a very strong inhibitory effect on AR activity. Several of these had anti-AR activity that significantly exceeded that of bicalutamide, one of the most potent anti-androgen drugs currently used to treat men with metastatic prostate cancer. These findings allow us to proceed further into the preclinical pharmacological testing proposed here and lay a foundation for the development of entirely novel and effective therapies capable of combatting prostate cancer even in its deadliest hormone-resistant forms.