Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif

Jehle, Katja; Cato, Laura; Neeb, Antje; Muhle‐Goll, Claudia; Jung, Nicole; Smith, Emmanuel W.; Buzón, Víctor; Carbo, Laia Rodriguez; Estébanez‐Perpiñá, Eva; Schmitz, Katja; Fruk, Ljiljana; Luy, Burkhard; Chen, Yu; Cox, Marc B.; Bräse, Stefan; Brown, Myles; Cato, Andrew C. B.

doi:10.1074/jbc.m113.534859

Cited by 47 publications

(70 citation statements)

References 69 publications

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“…More recently, the genomic binding profile of AR variants have also been explored and have been shown to compensate for full length AR in an endocrine therapy-like setting [22]. These studies have provided valuable insights in to the molecular biology and function of the AR and have identified several co-activators and corepressors that modulate AR transcriptional activity [23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

Nash

Boufaied

Mills

et al. 2018

Molecular and Cellular Endocrinology

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Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

Nash

Boufaied

Mills

et al. 2018

Molecular and Cellular Endocrinology

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“…This interaction plays an important role in the modulation of AR activity [109,110]. Different binding studies showed that compounds 11 and 14 blocked the interaction of Bag-1L motif peptides with the AR, implying that these compounds binds directly to the AR BF-3 site [103,108]. Taken together, these results show the great potential of the BF-3 site as a therapeutic target for the treatment of CRPC.…”

Section: <Insert Figure 4 (Single Column)>mentioning

confidence: 87%

“…Recent studies have demonstrated the important role of BF-3 in AR signaling regulation through the recruitment of AR coregulators such as FKBP52 [102] and Bag-1L [103] and crosstalk with the adjacent AF-2 [49,104]. Using a crystallographic screening approach, Estébanez-Perpiñá et al were the first to report compounds that allosterically inhibit the interaction of AR with coactivators by binding to the BF-3 site [49].…”

Section: Targeting the Binding Function 3 Sitementioning

confidence: 97%

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Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

Biron

Bédard

2016

The Journal of Steroid Biochemistry and Molecular Biology

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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.

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“…Mutations in NRs can affect the recruitment and activity of coregulators (Chen et al 2005, Duff & McEwan 2005, Prekovic et al 2016. Furthermore, there are also reports of mutations in the coregulators themselves, which also alters their activity in prostate cancer (Chmelar et al 2007, Jehle et al 2014.…”

Section: Nuclear Receptor Coregulator In Prostate Cancermentioning

confidence: 99%

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

Leach

Powell

Bevan

2016

Endocrine-Related Cancer

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Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease -hence the quest for new effective therapies for 'castrate-resistant' prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions has identified several other nuclear receptor signalling pathways as potential drivers or modulators of CRPC. The nuclear receptors constitute a large (48 members) superfamily of transcription factors sharing a common modular functional structure. Many of them are activated by the binding of small lipophilic molecules, making them potentially druggable. Even those for which no ligand exists or has yet been identified may be tractable to activity modulation by small molecules. Moreover, genomic studies have shown that in models of CRPC, other nuclear receptors can potentially drive similar transcriptional responses to the androgen receptor, while analysis of expression and sequencing databases shows disproportionately high mutation and copy number variation rates among the superfamily. Hence, the nuclear receptor superfamily is of intense interest in the drive to understand how prostate cancer recurs and how we may best treat such recurrent disease. This review aims to provide a snapshot of the current knowledge of the roles of different nuclear receptors in prostate cancer -a rapidly evolving field of research.

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Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif

Cited by 47 publications

References 69 publications

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

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