Androgen receptor–cofactor interactions as targets for new drug discovery

doi:10.1016/j.tips.2005.03.002

Trends in Pharmacological Sciences

Volume 26, Issue 5, May 2005, Pages 225-228

https://doi.org/10.1016/j.tips.2005.03.002 Get rights and content

Cofactor recruitment is a crucial regulatory step in nuclear receptor signal transduction. Given the obligate nature of interactions between cofactors and these receptors for transcriptional activity, it is likely that drugs that target coactivator interaction surfaces will function as pure antagonists with particular utility in the treatment of estrogen- and androgen-dependent cancers. Recent crystallographic analysis of one of the major protein–protein interaction surfaces on the androgen receptor has raised expectations that it will be possible to develop small-molecule antagonists that block cofactor interactions.

Section snippets

Cofactor recruitment is an obligate step in nuclear receptor action

The androgen receptor (AR) is a key regulator of processes involved in the growth of prostate cancer cells and thus has emerged as a primary therapeutic target in the management of this disease [1]. The AR is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. As a group, these receptors are involved in diverse activities but share a remarkable structural and functional similarity. In the absence of ligand they exist within target cells in a transcriptionally

The androgen receptor has distinct cofactor preferences

The crystal structure of the AR-LBD in the presence of its cognate agonist was solved several years ago, indicating that, like most nuclear receptors, this particular receptor appeared to contain a coactivator binding pocket 6, 7. However, it was later found that the AR does not abide by the rules established for other nuclear receptors and appears to interact with coactivators in a unique manner. Thus, although the AR-LBD has high sequence homology with the LBDs of other nuclear receptors and

The AR–cofactor interface as a target for drug discovery

All of the known drugs that target the nuclear receptor function by binding to the LBD, thereby inducing the conformational changes intended to either mimic or oppose the effect of the naturally occurring ligand. However, since the discovery of the receptor coactivators and the demonstration that the nuclear receptor–coactivator interface is relatively compact, these protein–protein interfaces are generally considered to be viable drug targets. Indeed, fueled by recent successes in the

Acknowledgements

This work is supported by grants from NCI CA95094 (CYC) and NIDDK DK-065251 (DMD).

References (24)

A.K. Shiau
The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen
Cell
(1998)
P.M. Matias
Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations
J. Biol. Chem.
(2000)
B. He
FXXLF and WXXLF sequences mediate the NH₂-terminal interaction with the ligand binding domain of the androgen receptor
J. Biol. Chem.
(2000)
C.L. Hsu
The use of phage display technique for the isolation of androgen receptor interacting peptides with (F/W)XXL(F/W) and FXXLY new signature motifs
J. Biol. Chem.
(2003)
B. He
Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance
Mol. Cell
(2004)
B. He
The FXXLF motif mediates androgen receptor-specific interactions with coregulators
J. Biol. Chem.
(2002)
E. Langley
Intermolecular NH2-/carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity
J. Biol. Chem.
(1998)
C.D. Chen
Molecular determinants of resistance to antiandrogen therapy
Nat. Med.
(2004)
D.P. McDonnell
Mining the complexities of the estrogen signaling pathways for novel therapeutics
Endocrinology
(2003)
D.M. Heery
A signature motif in transcriptional co-activators mediates binding to nuclear receptors
Nature
(1997)

R.T. Nolte

Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ

Nature

(1998)

J.S. Sack

Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone

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

(2001)

Cited by (73)

Molecular Mechanisms and Therapeutics for SBMA/Kennedy’s Disease
2019, Neurotherapeutics
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly 3 decades, there is no effective treatment for this disease, underscoring the complexity of the pathogenic mechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the current review, we provide an overview of the system-wide clinical features of SBMA, summarize the structure and function of the AR, discuss both gain-of-function and loss-of-function mechanisms of toxicity caused by polyQ-expanded AR, and describe the cell and animal models utilized in the study of SBMA. Additionally, we summarize previously conducted clinical trials which, despite being based on positive results from preclinical studies, proved to be largely ineffective in the treatment of SBMA; nonetheless, these studies provide important insights as researchers develop the next generation of therapies.
Steroid receptor/coactivator binding inhibitors: An update
2019, Molecular and Cellular Endocrinology
Citation Excerpt :
Indeed, several groups have shown that peptides that contain (F/W)XXLF motifs bind to the androgen receptor (He et al., 2004; Hur et al., 2004), and some of these motifs are expressed in coregulators that are unique to AR (He et al., 2002). AR can bind larger motifs selectively, and this size-exclusion principle may be used to develop AR-selective CBIs (Chang and McDonnell, 2005). Similarly to SERMs, selective androgen receptor modulators (SARMs) were developed in an effort to exhibit tissue-selectivity.
The purpose of this review is to highlight recent developments in small molecules and peptides that block the binding of coactivators to steroid receptors. These coactivator binding inhibitors bind at the coregulator binding groove, also known as Activation Function-2, rather than at the ligand-binding site of steroid receptors. Steroid receptors that have been targeted with coactivator binding inhibitors include the androgen receptor, estrogen receptor and progesterone receptor. Coactivator binding inhibitors may be useful in some cases of resistance to currently prescribed therapeutics. The scope of the review includes small-molecule and peptide coactivator binding inhibitors for steroid receptors, with a particular focus on recent compounds that have been assayed in cell-based models.
Development of selective androgen receptor modulators (SARMs)
2018, Molecular and Cellular Endocrinology
Citation Excerpt :
Coregulator Function. More than 200 AR-interacting proteins (both coactivators and corepressors) (Chang and McDonnell, 2005; Heinlein and Chang, 2002), including those with intrinsic functions such as histone acetyl transferase activity (SRCs, CBP) (Smith and O'Malley, 2004), histone deacetylase activity (NCoR, SMRT) (Smith and O'Malley, 2004), and other chromatin modifying functions (SWI/SNF/BRG) (Smith and O'Malley, 2004), have been identified. In addition to several coactivators that are shared by other steroid receptors, a few coactivators such as the ARA family members that exclusively activate the AR have been reported to be expressed in tissues such as prostate (Fujimoto et al., 1999; Kang et al., 1999).
The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.
Chemical analysis and potential endocrine activities of aluminium coatings intended to be in contact with cosmetic water
2017, Journal of Pharmaceutical and Biomedical Analysis
The objective of the work was to check the presence of Non-Intended Added Substances (NIAS) with hormonal activities in aluminium coatings extracts coded: AA, BBF, MC and RR, furnished by four different suppliers. Water samples were prepared at room temperature or at 40 °C for three months to verify the storage effect on the coatings. Solid phase extraction was used to concentrate and to extract coating substances. Hormonal activities were checked in vitro using reporter gene bioassays. Except BBF, all extracts induced a weak but significant estrogenic agonist activity in the human cell line. Using an estrogenic antagonist (ICI-182, 780), the answer was demonstrated specific in the bioassay. RR was the only extract to induce a concentration dependent anti-androgenic response in the MDA-KB2 cell line. Analysis performed using GC–MS and HPLC–MS detected 12 substances in most of the extracts. 8 NIAS were present. Among them, 4 were identified with certainty: HMBT, BGA, DCU and BPA. Estrogenic potency was BPA > DCU > BGA > HMBT. HMBT was also anti-androgenic at high concentration. Combining chemical analysis and bioassays data, we demonstrated that in the RR and the RR40 extracts, the observed estrogenic response was mainly due to BPA, the anti-androgenic activity of RR could be due to a synergism between HMBT and BPA. For MC and AA, estrogenic responses appear to be due to the presence of DCU. Except BBF, storage conditions tended to increase estrogenic activities in all extracts. However, in term of risk assessment, activities observed were negligible. This work demonstrated that sensitive bioassays are pertinent tools in complement to chemical analysis to monitor and check the presence of NIAS with hormonal activity in coating extracts.
Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer
2016, Journal of Steroid Biochemistry and Molecular Biology
The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein–protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer.
Novel yeast-based strategy unveils antagonist binding regions on the nuclear xenobiotic receptor PXR
2013, Journal of Biological Chemistry
The pregnane X receptor (PXR) is a master regulator of xenobiotic metabolism, and its activity is critical toward understanding the pathophysiology of several diseases, including inflammation, cancer, and steatosis. Previous studies have demonstrated that ketoconazole binds to ligand-activated PXR and antagonizes receptor control of gene expression. Structure-function as well as computational docking analysis suggested a putative binding region containing critical charge clamp residues Gln-272, and Phe-264 on the AF-2 surface of PXR. To define the antagonist binding surface(s) of PXR, we developed a novel assay to identify key amino acid residues on PXR based on a yeast two-hybrid screen that examined mutant forms of PXR. This screen identified multiple “gain-of-function” mutants that were “resistant” to the PXR antagonist effects of ketoconazole. We then compared our screen results identifying key PXR residues to those predicted by computational methods. Of 15 potential or putative binding residues based on docking, we identified three residues in the yeast screen that were then systematically verified to functionally interact with ketoconazole using mammalian assays. Among the residues confirmed by our study was Ser-208, which is on the opposite side of the protein from the AF-2 region critical for receptor regulation. The identification of new locations for antagonist binding on the surface or buried in PXR indicates novel aspects to the mechanism of receptor antagonism. These results significantly expand our understanding of antagonist binding sites on the surface of PXR and suggest new avenues to regulate this receptor for clinical applications.

View all citing articles on Scopus

View full text

Trends in Pharmacological Sciences

Research FocusAndrogen receptor–cofactor interactions as targets for new drug discovery

Section snippets

Cofactor recruitment is an obligate step in nuclear receptor action

The androgen receptor has distinct cofactor preferences

The AR–cofactor interface as a target for drug discovery

Acknowledgements

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Molecular determinants of resistance to antiandrogen therapy

Nat. Med.

Mining the complexities of the estrogen signaling pathways for novel therapeutics

Endocrinology

A signature motif in transcriptional co-activators mediates binding to nuclear receptors

Nature

Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ

Nature

Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone

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

Research Focus
Androgen receptor–cofactor interactions as targets for new drug discovery