Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening.

The androgen receptor (AR) is the best studied drug target
for
the treatment of prostate cancer. While there are a number of drugs
that target the AR, they all work through the same mechanism of action
and are prone to the development of drug resistance. There is a large
unmet need for novel AR inhibitors which work through alternative
mechanism­(s). Recent studies have identified a novel site on the AR
called binding function 3 (BF3) that is involved into AR transcriptional
activity. In order to identify inhibitors that target the BF3 site,
we have conducted a large-scale in silico screen followed by experimental
evaluation. A number of compounds were identified that effectively
inhibited the AR transcriptional activity with no obvious cytotoxicity.
The mechanism of action of these compounds was validated by biochemical
assays and X-ray crystallography. These findings lay a foundation
for the development of alternative or supplementary therapies capable
of combating prostate cancer even in its antiandrogen resistant forms.