A Cellular Conformation-Based Screen for Androgen Receptor Inhibitors

Jones, Jeremy O.; Diamond, Marc I.

doi:10.1021/cb800054w

Cited by 39 publications

(68 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Encouragingly, drugs modulating AR conformation and activity, subsequent to hormone binding, have been previously found [33]. Our data make it difficult to infer the potential effects of such selective modulators on GR activity.…”

Section: Implications Of Gr Monomers For Physiologymentioning

confidence: 89%

Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes

et al. 2014

View full text Add to dashboard Cite

Background: Glucocorticoid receptor (GR) is a hormone-activated, DNA-binding transcriptional regulatory factor that controls inflammation, metabolism, stress responses, and other physiological processes. In vitro, GR binds as an inverted dimer to a motif consisting of two imperfectly palindromic 6 bp half sites separated by 3 bp spacers. In vivo, GR employs different patterns of functional surfaces of GR to regulate different target genes. The relationships between GR genomic binding and functional surface utilization have not been defined.

show abstract

Section: Implications Of Gr Monomers For Physiologymentioning

confidence: 89%

Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The most potent inhibitors targeted pathways known to influence the activity of AR and many other proteins (actinomycin (RNA synthesis), cucurbitacin (JAK/STAT3), and radicol (HSP90)) (22).…”

Section: Small Molecules That Target Armentioning

confidence: 99%

Small Molecule Inhibitors as Probes for Estrogen and Androgen Receptor Action

Shapiro

Mao

Cherian

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Within the large nuclear receptor family, estrogen (ER) 2 and androgen (AR) receptors are unusual in their ability to stimulate cell proliferation. The central roles played by ER␣ and AR in most cases of breast and prostate cancer led to an intense effort to identify agents that modulate receptor activity. The availability of substantial information on the interaction of agonist ligands with ER␣ and AR led to a primary focus on identification of small molecules that act by competing with natural hormones for binding in the ligand-binding pocket of the receptors. This fruitful approach was followed by development of agents that act by inhibiting key enzymes in estrogen synthesis. Although these approaches to development of clinically useful agents remain productive, as shown by recent development of an improved competitive ligand for androgens (1) and an inhibitor of androgen production in prostate tumors (2), their current potential for illuminating novel mechanisms of ER and AR action is limited. Here, we focus on small molecules modulators of ER and AR activity that act outside of the ligand-binding pocket. Some of the sites targeted in attempts to antagonize ER action in breast cancer are illustrated in Fig.

show abstract

“…This induces an intramolecular conformation change in AR that brings the amino (N) and carboxy (C) termini into close proximity. This occurs with a t 1/2 of approximately 3.5 min in cells treated with DHT (5), and does not occur in cell lysates (6), suggesting that the induced conformation change is not protein autonomous, but depends on additional cellular factors. Activated AR accumulates in the nucleus, where it binds to DNA as a homodimer at specific androgen response elements to regulate gene expression.…”

mentioning

confidence: 98%

“…These inhibitors might lead to new therapeutic approaches to treat androgen-dependent diseases, and new insights into the molecular mechanisms that control AR activity. We previously used a cell-based assay of ligand-induced conformational change in AR to identify multiple non-competitive antagonists (6). Here, we evaluate the 2 most potent AR inhibitors, pyrvinium pamoate (PP), a Food and Drug Administration-approved drug (8,9), and harmol hydrochloride (HH), a natural product (10).…”

mentioning

confidence: 99%

Non-competitive androgen receptor inhibition in vitro and in vivo

Jones

Bolton

Huang³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

View full text Add to dashboard Cite

Androgen receptor (AR) inhibitors are used to treat multiple human diseases, including hirsutism, benign prostatic hypertrophy, and prostate cancer, but all available anti-androgens target only ligand binding, either by reduction of available hormone or by competitive antagonism. New strategies are needed, and could have an important impact on therapy. One approach could be to target other cellular mechanisms required for receptor activation. In prior work, we used a cell-based assay of AR conformation change to identify non-ligand inhibitors of AR activity. Here, we characterize 2 compounds identified in this screen: pyrvinium pamoate, a Food and Drug Administration-approved drug, and harmol hydrochloride, a natural product. Each compound functions by a unique, non-competitive mechanism and synergizes with competitive antagonists to disrupt AR activity. Harmol blocks DNA occupancy by AR, whereas pyrvinium does not. Pyrvinium inhibits AR-dependent gene expression in the prostate gland in vivo, and induces prostate atrophy. These results highlight new therapeutic strategies to inhibit AR activity.antagonist ͉ harmol ͉ pyrvinium T he androgen receptor (AR) is a member of the nuclear hormone receptor superfamily, which consists of a large group of ligand-regulated transcription factors. AR is expressed in many tissues and influences an enormous range of physiologic processes such as cognition, muscle hypertrophy, bone density, and prostate growth and differentiation (1). However, AR signaling is directly linked to numerous diseases, including benign prostatic hyperplasia, alopecia, and hirsutism (2). AR signaling also drives the proliferation of prostate cancer, even in the setting of therapies that reduce systemic hormone ligand levels, making AR the major therapeutic target for this malignancy (3).Before ligand binding, AR associates with a complex of cytoplasmic factors and molecular chaperones that maintain the receptor in a high-affinity ligand binding conformation (4). AR signaling is initiated by binding of testosterone or the more potent dihydrotestosterone (DHT). This induces an intramolecular conformation change in AR that brings the amino (N) and carboxy (C) termini into close proximity. This occurs with a t 1/2 of approximately 3.5 min in cells treated with DHT (5), and does not occur in cell lysates (6), suggesting that the induced conformation change is not protein autonomous, but depends on additional cellular factors. Activated AR accumulates in the nucleus, where it binds to DNA as a homodimer at specific androgen response elements to regulate gene expression. Transcriptional control by AR results from complex interactions with positive (i.e., co-activator) and negative (i.e., co-repressor) factors (1). These co-regulatory factors fine-tune AR activity, and AR can even be activated in the absence of ligand by certain cross-talk pathways (7).Although AR activity is highly regulated, with many possible points for intervention, all existing approaches to block AR signaling ultimately target ligand bin...

show abstract

A Cellular Conformation-Based Screen for Androgen Receptor Inhibitors

Cited by 39 publications

References 38 publications

Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes

Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes

Small Molecule Inhibitors as Probes for Estrogen and Androgen Receptor Action

Non-competitive androgen receptor inhibition in vitro and in vivo

Contact Info

Product

Resources

About