Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers

Roshan-Moniri, Mani; Hsing, Michael; Butler, Miriam; Cherkasov, Artem; Rennie, Paul S.

doi:10.1016/j.ctrv.2014.10.005

Cited by 29 publications

(13 citation statements)

References 227 publications

(242 reference statements)

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“…Although the modifications tested to date have not yet resulted in significant sub-micromolar activity, these derivatives do provide a working structure-activity relationship that will guide future medchem efforts. DNA binding domains of transcription factors are often conserved and exhibit low rates of mutations as a structural compromise is likely to translate into a loss of function [46]. Targeting such DNA-interacting regions may increase the value of the corresponding drugs due to less mutation-driven resistance, but also makes direct assessment of binding specificity by mutagenesis challenging.…”

Section: Discussionmentioning

confidence: 99%

Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

et al. 2017

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Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease development and progression. This study describes the discovery and characterization of a new class of small molecule ERG antagonists identified through rational in silico methods. These antagonists are designed to sterically block DNA binding by the ETS domain of ERG and thereby disrupt transcriptional activity. We confirmed the direct binding of a lead compound, VPC-18005, with the ERG-ETS domain using biophysical approaches. We then demonstrated VPC-18005 reduced migration and invasion rates of ERG expressing prostate cancer cells, and reduced metastasis in a zebrafish xenograft model. These results demonstrate proof-of-principal that small molecule targeting of the ERG-ETS domain can suppress transcriptional activity and reverse transformed characteristics of prostate cancers aberrantly expressing ERG. Clinical advancement of the developed small molecule inhibitors may provide new therapeutic agents for use as alternatives to, or in combination with, current therapies for men with ERG-expressing metastatic castration-resistant prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

et al. 2017

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“…Accruing evidences in recent years strongly suggest that orphan NRs play important roles in cancer development and progression as shown by their altered expressions and dysregulated signaling pathways involved in multiple cancers [6,7]. Although these orphan NRs are constitutively active and independent of any physiological ligands, there are increasing studies showing that orphan NRs are druggable and regarded as prospective novel cancer drug targets [8], as evidenced by some synthetic or natural compounds which can directly bind to these orphan NRs and modulate their activities. In this review, we summarized the emerging roles of orphan NRs in prostate cancer.…”

Section: Nuclear Receptors and Orphan Nuclear Receptorsmentioning

confidence: 99%

The emerging roles of orphan nuclear receptors in prostate cancer

Cheung

Wang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer.

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“…In addition to androgen-signaling pathways, estrogen-signaling pathways are implicated in the development of prostate cancer ( 1 ), and estrogen has been used for the treatment of advanced prostate cancer ( 74 ). The direct effect of estrogens on normal and malignant prostate tissues is assumed to be mediated through ERα and ERβ ( 75 , 76 ).…”

Section: Errs In Prostate Cancermentioning

confidence: 99%

“…Among the 48 members of the nuclear receptor superfamily, the estrogen receptor (ER)-like subfamily (NR3) is one of the seven subfamilies and is composed of three groups: ERs(NR3A), estrogen-related receptors (ERRs or NR3B), and 3-ketosteroid receptors (NR3C), which include the androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). ERRs were initially thought to share a common biological function with ERs, but unexpectedly, they do not bind to estrogen or endogenous ER ligands and are considered orphan nuclear receptors ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Estrogen-Related Receptors in Breast Cancer and Prostate Cancer

Misawa

Inoue

2015

Front. Endocrinol.

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Estrogen-signaling pathways are implicated in the development of breast cancer and prostate cancer. Various studies have focused on additional signaling pathways, mediated by estrogen-related receptors (ERRs). ERRs are constitutively active receptors that share a high degree of homology with the classical estrogen receptors (ERs). However, they do not bind to estrogen, while ERs do. ERRs are involved in the development of alternative pathways that lead to the development of cancer and are regarded as potential therapeutic targets for the treatment of breast cancer and prostate cancer that do not respond to conventional therapies. In this review, we first present general structural features of ERRs. Then, we focus on breast cancer and prostate cancer, which are primarily hormone-dependent cancers, and summarizes recent progress in elucidating the involvement of each ERR in these two types of malignancies.

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Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers

Cited by 29 publications

References 227 publications

Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

The emerging roles of orphan nuclear receptors in prostate cancer

Estrogen-Related Receptors in Breast Cancer and Prostate Cancer

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