Mechanism of Androgen Receptor Antagonism by Bicalutamide in the Treatment of Prostate Cancer

Abstract

The androgen receptor (AR) plays a key role in a regulating gene expression in a variety of tissues, including the prostate. In the latter role it is one of the primary targets in the development of new chemotherapeutics for treatment of prostate cancer, as well as being the target of the most widely prescribed current drug, bicalutamide (Bcu), for this disease. In view of it’s importance, and the absence of a crystal structure for any antagonist-AR complex, we have carried out a series of molecular dynamics based simulations of the AR-Bcu complex and quantum mechanical (QM) calculations of Bcu, to elucidate the structural basis for antagonism of this key target. The structures which emerge show that bicalutamide antagonizes AR by accessing an additional binding pocket (B-site) adjacent to the hormone binding site (HBS), induced by displacing helix 12. This distorts the coactivator binding site and results in the inactivation of transcription. An alternative equienergetic conformational state of bicalutamide was found to bind in an expanded hormone pocket without materially perturbing either helix 12 or the coactivator binding site. Thus both the structural basis of antagonism and the mechanism underlying agonist properties displayed by bicalutamide in different environments may be rationalized in terms of these structures. In addition the antagonist structure and especially the induced second site (B-site) provides a structural framework for the design of novel antiandrogens.

Binding of a Cyano- and Fluoro-containing Drug Bicalutamide to Cytochrome P450 46A1

“…In contrast, in the present study the drug (BIC) likely folds rather than unfolds once in the CYP46A1 active site, and remarkably, this folding is accomplished without the large scale conformational changes in the P450. Quantum mechanical calculations (42) indicate that BIC has two energetic minima: one when it is in the extended conformation, similar to that observed in the AR structure and the second minimum when it is in the folded conformation, similar to those in some of the structures when BIC was crystallized alone (39 -41) or in complex with CYP46A1. The present work shows that in CYP46A1, local movements of amino acid residues induce BIC folding in a conformation that is energetically less favorable, likely because it is stabilized by the hydrogen bonds between the BIC functionalities and the protein side chains and water.…”

“…B, in co-complex with the AR (37). C-F, in structures of BIC alone (39 -41), and G, in the computed structure (42). The nitrogen, oxygen, fluorine and sulfur atoms are in blue, red, pale cyan, and yellow, respectively.…”

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

“…The discrepancy in results may be due to differences in the mechanisms of action of the two AR antagonists. Bicalutamide permits AR nuclear localization and binding to chromatin, recruiting corepressors rather than coactivators, whereas enzalutamide inhibits nuclear localization and DNA binding [42]. …”

Androgen receptor antagonists for prostate cancer therapy

“…In absence of antagonist-bound AR crystals, molecular modeling techniques have predicted that, for the AR, a displacement of helix 12 could occur in the presence of antiandrogens, although involvement of residues in helix 5 and helix 11 cannot be excluded (Georget et al 2002, Bohl et al 2005a, Bisson et al 2008, Osguthorpe & Hagler 2011. The conformation of the receptor induced by antagonists results in the inhibition of many required actions of the AR, such as inhibition of entry to the cell nucleus, binding to DNA response elements, recruitment of coactivators, etc.…”

“…Bicalutamide When bic binds to the ligand-binding pocket of the AR, a displacement of helix 12 and consequently a distortion of the coactivator platform were suggested by molecular dynamics-based simulations (Osguthorpe & Hagler 2011). Furthermore, it leads to the assembly of a transcriptionally inactive complex due to the inability of the bic-bound AR to recruit coactivators and/or the preferential recruitment of corepressors, NCoR and SMRT (Masiello et al 2002).…”