Main Area of Interest
Prostate cancer is one of the leading causes of death in men in the western world. Current available therapy is androgen deprivation with androgen receptor antagonists like bicalutamide and flutamide. However, androgen resistance, which causes relapse of the disease, usually occurs. The binding of natural agonists testosterone (T) and dihydrotestosterone (DHT) to the ligand binding pocket of the AR causes a shift in position of the helix 12 and the formation of a hydrophobic pocket called activating function 2 (AF2) necessary for the binding of coactivators. The identification of small molecules which are able to disrupt AR-coactivator interaction represent a novel therapeutical approach which will overcome the problem of androgen resistance.The main goal of my project is focused on the identification of alternative site modulators of the Androgen Receptor Ligand Binding Domain (AR-LBD) which are able to target the surface of the receptor by disrupting co-activator recruitment.
The disruption of co-activator binding was assessed for a series of analogs of the two initial hits previously identified with the MDG through virtual screening techniques using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) as a primary screen.
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