Endocrine Abstracts

The role of the androgen receptor (AR) in the progression of prostate cancer (PCa) is well established. Competitive inhibition of the AR ligand binding domain (LBD) has been the staple of antiandrogen therapies employed to combat the disease in recent years. However their efficacy has often been limited by the emergence of resistance, mediated through point mutations and receptor truncations. As a result the prognosis for patients with malignant castrate resistant disease remains poor. The amino terminal domain (NTD) of the AR has been shown to be critical for AR function. Its modular activation function (AF-1) is important for both gene regulation and participation in protein-protein interactions. However due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has in the past been dismissed. The recent emergence of the small molecule EPI-001 has provided evidence that the AR-NTD can be targeted therapeutically, independent of the LBD. We have developed a phenotypic cell based assay for novel AR modulators and used this to screen a library of over 7,000 chemically diverse molecules. We have identified and begun characterising four novel compounds with the potential to inhibit the AR. Targeting of the AR-NTD has the potential to disrupt multiple inter-molecular interactions between the AR and its coregulatory binding partners, in addition to intra-molecular cross-talk between the domains of the AR. Therapeutics targeting these protein-protein interactions, or the NTD directly should also have efficacy against emerging AR splice variants which may play a role in PCa progression.

Funding: BBSRC, IOmet Pharma, Friend of Anchor.

Presenting Author: IJ McEwan, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. Email: [email protected]