The Nuclear Receptor Superfamily and Drug Discovery

Moore, John T.; Collins, Jon L.; Pearce, Kenneth H.

doi:10.1002/cmdc.200600006

Cited by 139 publications

(67 citation statements)

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“…NR signaling involves ligand-triggered protein-protein interaction to assemble a multiprotein complex that regulates transcription in response to hormone binding (2,55,56). Structurally, NRs interact with coactivators through similar surfaces, with a shallow hydrophobic groove on the surface binding to an amphipathic ␣-helical motif on the coactivator, burying the three leucines into the hydrophobic surface of the NR box (26,27).…”

Section: Discussionmentioning

confidence: 99%

“…The nuclear hormone receptors (NR) 2 are transcription factors that are a major focus for drug development in the pharmaceutical industry for diverse diseases including metabolic disease, immunology, reproductive health, and cancer (1)(2)(3). Most NR modulators are ligand analogs; tamoxifen (4) and faslodex (5) bind the estrogen receptor (ER), hydroxyflutamide (6) and bicalutamide (7,8) target the androgen receptor (AR), and rosiglitazone (9,10) and pioglitazone (11,12) bind the peroxisome proliferator-activated receptor ␥ (PPAR␥).…”

mentioning

confidence: 99%

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Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Hwang

Huang

Arnold

et al. 2011

Journal of Biological Chemistry

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Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TR␤ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T 3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPAR␥ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TR␤ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TR␤ to disrupt SRC2 association.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Hwang

Huang

Arnold

et al. 2011

Journal of Biological Chemistry

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“…Ligand activation of NRs induces an active conformation, enabling transcriptional regulation (Moore et al 2006). Within the NR superfamily, two modes of action exist.…”

Section: Introductionmentioning

confidence: 99%

Nuclear receptor research in zebrafish

Schaaf

2017

Journal of Molecular Endocrinology

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Nuclear receptors (NRs) form a superfamily of transcription factors that can be activated by ligands and are involved in a wide range of physiological processes. NRs are well conserved between vertebrate species. The zebrafish, an increasingly popular animal model system, contains a total of 73 NR genes, and orthologues of almost all human NRs are present. In this review article, an overview is presented of NR research in which the zebrafish has been used as a model. Research is described on the three most studied zebrafish NRs: the estrogen receptors (ERs), retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs). The studies on these receptors illustrate the versatility of the zebrafish as a model for ecotoxicological, developmental and biomedical research. Although the use of the zebrafish in NR research is still relatively limited, it is expected that in the next decade the full potential of this animal model will be exploited.

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“…5,6 Physiological effects of progesterone are mediated by multiple mechanisms of action; mainly through the activation of the progesterone receptor (PR), 7 a member of the oxosteroid receptor family (oSR), which also includes receptors for the mineralocorticoids (MR), glucocorticoids (GR) and androgens (AR). 8 The oSRs are soluble intracellular proteins that act mainly as ligand regulated transcription factors, regulating specific gene expression in most mammalian cells. 9 Structurally, oSRs are modular proteins organized into three major domains: an N-terminal activation function-1 (AF-1), a central DNA binding domain (DBD) and a C-terminal ligand binding domain (LBD).…”

Section: Introductionmentioning

confidence: 99%