THE INTRINSICALLY DISORDERED AMINO TERMINAL DOMAIN OF STEROID HORMONE RECEPTORS AS A NOVEL DRUG TARGET: IDENTIFICATION OF SMALL MOLECULE INHIBITORS

Iain J. McEwan

Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK

Abstract

The role of the androgen receptor (AR) in the progression of prostate cancer (PCa) is well established and competitive inhibition of hormone binding has been the staple of antiandrogen therapies. However their efficacy has often been limited by the emergence of resistance, mediated through receptor point mutations and truncations.

The amino terminal domain (NTD) of the AR has been shown to be critical for AR-dependent gene regulation. 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 hormone binding. We have developed a phenotypic cell based assay for novel AR modulators and used this to screen a library of chemically diverse molecules. We have identified and begun characterising 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. Directly inhibiting the NTD will also have efficacy against emerging AR splice variants, lacking the ligand-binding domain, which play a role in PCa progression.

Keywords: Receptor, domain, prostate, candidate, efficacy.