3 research outputs found
Current and emerging approaches to noncompetitive AR inhibition
The Androgen Receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). Current standard of care therapies target the ligand-binding domain of the receptor, and afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current anti-androgens show promise for overcoming treatment resistance. In this review we present an authoritative summary of molecules that non-competitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential future therapies. The overall quality of lead candidates in the area of non-competitive AR inhibition is discussed, and identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned for first in human applications
Structure–Activity Relationships in Non-Ligand Binding Pocket (Non-LBP) Diarylhydrazide Antiandrogens
We report the synthesis and a study
of the structure–activity
relationships of a new series of diarylhydrazides as potential selective
non-ligand binding pocket androgen receptor antagonists. Their biological
activity as antiandrogens in the context of the development of treatments
for castration resistant prostate cancer was evaluated using <i>in vitro</i> time resolved fluorescence resonance energy transfer
and fluorescence polarization on target assays. Additionally, a theoretical
study combining docking and molecular dynamics methods was performed
to provide insight into their mechanism of action as a basis for further
lead optimization studies