Chemistry and Structural Biology of Androgen Receptor

Gao, Wenqing; Bohl, Casey E.; Dalton, James T.

doi:10.1021/cr020456u

Cited by 469 publications

(411 citation statements)

References 152 publications

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“…The androgen receptor (AR) belongs to the subfamily of steroid receptors and its ligands include testosterone and 5a-dihydrotestoterone (5a-DHT). AR-dependent gene expression in androgen target tissues, including prostate, skeletal muscle, liver and central nervous system is responsible for male sexual differentiation and male pubertal changes (Gao et al, 2005). In addition, functional androgen receptor signalling is necessary for the development and maintenance of prostate cancer and antagonists are currently used for therapy (Gao et al, 2005).…”

Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

“…AR-dependent gene expression in androgen target tissues, including prostate, skeletal muscle, liver and central nervous system is responsible for male sexual differentiation and male pubertal changes (Gao et al, 2005). In addition, functional androgen receptor signalling is necessary for the development and maintenance of prostate cancer and antagonists are currently used for therapy (Gao et al, 2005). The ability of androgens to inhibit apoptosis in both normal and malignant prostatic cells has been well documented.…”

Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

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FOXO-binding partners: it takes two to tango

van der Vos,

Coffer

2008

Oncogene

187

161

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Modulation FOXO transcription factor activities can lead to a variety of cellular outputs resulting in changes in proliferation, apoptosis, differentiation and metabolic responses. Although FOXO proteins all contain an identical DNA-binding domain their cellular functions appear to be distinct, as exemplified by differences in the phenotype of Foxo1, Foxo3 and Foxo4 null mutant mice. While some of these differences may be attributable to the differential expression patterns of these transcription factors, many cells and tissues express several FOXO isoforms. Recently it has become clear that FOXO proteins can regulate transcriptional responses independently of direct DNA-binding. It has been demonstrated that FOXOs can associate with a variety of unrelated transcription factors, regulating activation or repression of diverse target genes. The complement of transcription factors expressed in a particular cell type is thus critical in determining the functional end point of FOXO activity. These interactions greatly expand the possibilities for FOXO-mediated regulation of transcriptional programmes. This review details currently described FOXO-binding partners and examines the role of these interactions in regulating cell fate decisions.

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Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

FOXO-binding partners: it takes two to tango

van der Vos,

Coffer

2008

Oncogene

187

161

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“…3 Androgen exerts its action through the androgen receptor (AR), a member of the nuclear receptor superfamily that acts as a ligand-dependent transcription factor. 4,5 The most prevalent androgen in the serum, testosterone, is converted by the enzyme 5-a-reductase in both normal prostatic epithelial and prostate cancer cells to dihydrotestosterone (DHT), a potent androgen that is a high affinity ligand of the AR. 6 Ligand binding displaces the receptor from inhibitory heat shock proteins, whereupon the receptor rapidly translocates to the nucleus, binds DNA at androgen responsive elements (AREs), recruits coactivators to enhance its transactivation function, and initiates a program of gene transcription that results in a myriad of cellular outcomes.…”

Section: Introductionmentioning

confidence: 99%

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

Comstock¹,

Knudsen²

2007

Cell Cycle

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“…6,7 The possibility of obtaining compounds having tissueselective activities that are different from that of the endogenous benchmark testosterone might derive from the fact that typical AR receptor activation, which is initiated by the binding of a molecule with affinity for the AR to the AR ligand binding domain, is then followed by a rather remarkable, coordinated series of interactions: These may include a change in receptor topology, dissociation of heat shock proteins, receptor dimerization, receptor phosphorylation, rapid-signaling events, translocation to the nucleus (AR), association with many different coregulatory proteins to form a transcriptional complex that results in the activation or suppression of RNA synthesis from AR-modulated genes, and finally receptor degradation. 8 Since each receptor-ligand complex topology is unique to that ligand structure, one can appreciate that the interaction of any particular ligand-receptor complex with coregulatory proteins is likely to be unique to that ligand as well. Furthermore, because the expression level of AR, the constellation and expression level of coregulatory proteins, and the patterns of post-transcriptional regulatory events differ in each type of androgen target cell, and the topography of AR regulatory sites in the genome differs at each gene, this remarkable choreography of events and interactions provides a rich environment within which one might search for SARMs having a desirable pattern of tissue-selective pharmacology, such as high anabolic but limited androgenic activity.…”

mentioning

confidence: 99%

Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140

Miller

Shomali

Lyttle

et al. 2010

ACS Med. Chem. Lett.

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This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.KEYWORDS Androgen, SARM, cachexia, oxadiazole, Herschberger assay, primate T he androgen receptor (AR) is a member of the steroid hormone nuclear receptor superfamily that includes estrogen, progestin, glucocorticoid and mineralocorticoid receptors. 1 The binding of the prototypical, endogeneously produced androgen testosterone (1) and the important active metabolite dihydrotestosterone (2) to AR initiates a remarkably diverse array of biological activities that can vary according to a subject's sex, age and hormonal status. The activity of AR is critical to normal human sexual development and function, but beyond this signature role, AR activation also has important effects on diverse targets such as bone, liver, muscle and the central nervous system. 2,3 The therapeutic potential of androgen signaling is well-appreciated in the medicinal chemistry community, and for quite some time, chemists have sought compounds that selectively stimulate muscle and bone growth while minimizing the proliferative and/or hypertrophic effects on sex tissues such as the prostate in males and clitoris in females. 4,5 Such compounds have been termed selective androgen receptor modulators or SARMs. In this regard, the prototypical and endogenous androgen, testosterone, is considered to be a logical benchmark comparator. Compound 3 is the GTx SARM S-22 and compound 4 is the BMS SARM 562929, both of which have been reported in the literature as being orally active compounds with selectivity for muscle over prostate relative to testosterone in various preclinical models. 6,7 The possibility of obtaining compounds having tissueselective activities that are different from that of the endogenous benchmark testosterone might derive from the fact that typical AR receptor activation, which is initiated by the binding of a molecule with affinity for the AR to the AR ligand binding domain, is then followed by a rather remarkable, coordinated series of interactions: These may include a change in receptor topology, dissociation of heat shock proteins, receptor dimerization, receptor phosphorylation, rapid-signaling events, translocation to the nucleus (AR), association with many different coregulatory proteins to form a transcriptional complex that results in the activation or suppression of RNA synthesis from AR-modulated genes, and finally receptor degradation. 8 Since each receptor-ligand complex topology is unique to that ligand structure, one can appreciate that the interaction of any particular ligand-receptor complex with coregulatory proteins is likely to be unique to that ligand as well. Furthermore, because the expression level of AR, the constellation and expression level of coregulatory proteins, and the patterns of post-transcriptional regulatory events differ in each type of androgen...

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Chemistry and Structural Biology of Androgen Receptor

Cited by 469 publications

References 152 publications

FOXO-binding partners: it takes two to tango

FOXO-binding partners: it takes two to tango

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140

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