Identification of Novel
Androgen Receptor Antagonists
Using Structure- and Ligand-Based Methods
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Abstract
Androgen receptor (AR) plays a critical role in the development
and progression of prostate cancer (PCa). The AR hormone-binding site
(HBS) is intensively studied and represents the target area for current
antiandrogens including Bicalutamide and structurally related Enzalutamide.
As resistance to antiandrogens invariably emerges in advanced prostate
cancer, there exists a high medical need for the identification and
development of novel AR antagonists of different chemotypes. Given
the wealth of structural information on the AR in complex with a variety
of ligands, we have applied an integrated structure- and ligand-based
virtual screening methodology to identify novel AR antagonists. Virtual
hits generated by a consensus voting approach were experimentally
evaluated and resulted in the discovery of a number of structurally
diverse submicromolar antagonists of the AR. In particular, one identified
compound demonstrated anti-AR potency <i>in vitro</i> that
is comparable to the clinically used Bicalutamide. These results set
a ground for the development of novel classes of PCa drugs that are
structurally different from current AR antagonists