The Nuclear Receptor Superfamily and Drug Discovery

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

doi:10.1002/9783527619375.ch15c

Cited by 13 publications

(19 citation statements)

References 124 publications

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“…The LBD is the primary target for NR drug discovery (Hall & McDonnell 2005, Moore et al 2006. In most traditional approaches, pharmaceuticals designed to modulate NR activity compete for access to the cognate ligand-binding pocket.…”

mentioning

confidence: 99%

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Kojetin¹,

Burris²,

Jensen³

et al. 2008

Endocrine Related Cancer

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A number of studies have reported on the unusual pharmacological behavior of type I antiestrogens, such as tamoxifen. These agents display mixed agonist/antagonist activity in a dose-, cell-, and tissue-specific manner. Consequently, many efforts have been made to develop so-called 'pure' antiestrogens that lack mixed agonist/antagonist activity. The recent report of the structure of estrogen receptor (ER) b with a second molecule of 4-hydroxytamoxifen (HT) bound in the coactivator-binding surface of the ligand-binding domain (LBD) represents the first direct example of a second ER ligand-binding site and provides insight into the possible origin of mixed agonist/antagonist activity of type I antiestrogens. In this review, we summarize the biological reports leading up to the structural conformation of a second ER ligand-binding site, compare the ERb LBD structure bound with two HT molecules to other ER structures, and discuss the potential for small molecular inhibitors designed to directly inhibit ER-coactivator and, more generally, nuclear receptor (NR)-coactivator interactions. The studies support a departure from the traditional paradigm of drug targeting to the ligand-binding site, to that of a rational approach targeting a functionally important surface, namely the NR coactivator-binding (activation function-2) surface. Furthermore, we provide evidence supporting a reevaluation of the strict interpretation of the agonist/antagonist state with respect to the position of helix 12 in the NR LBD.

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mentioning

confidence: 99%

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Kojetin¹,

Burris²,

Jensen³

et al. 2008

Endocrine Related Cancer

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“…8.1. The AF1 and hinge regions of NRs are the most divergent in sequence and length across the superfamily, are considered intrinsically disordered (Krasowski et al 2008), and their function and significance have been reviewed (Moore et al 2006;Warnmark et al 2003;Tremblay et al 1999;Clinckemalie et al 2012;Zwart et al 2010). The DBD is the most highly conserved sequence among NRs and contains two zinc finger motifs to bind distinct DNA response elements.…”

Section: Nuclear Receptorsmentioning

confidence: 98%

RORs in Autoimmune Disease

Chang

Rosen

Griffin

2014

Current Topics in Microbiology and Immunology

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The retinoic acid receptor-related orphan receptor (ROR) subfamily of nuclear receptors are transcription factors involved in the maintenance of circadian rhythm and are essential for proper immune function. The T cell-specific isoform, RORγt, is required for T helper 17 cells (TH17) development and it has been implicated in the pathogenesis of autoimmune diseases including multiple sclerosis and rheumatoid arthritis. Thus, pharmacological repression of RORγt may provide a strategy for therapeutic intervention in autoimmune disorders. This chapter provides a summary of the current status for target validation and development of new chemical entities targeting RORγt.

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“…First, SF-1 and RORA are both transcriptionally active in cell-based functional assays (Carlberg et al, 1994;Mellon and Bair, 1998) and they both bind DNA as monomers, whereas most of NRs do so only in a homo-or heterodimerized state (Giguère, 1999). Second, their ligand binding domains may be responsive to smallmolecule ligands (Kallen et al, 2004;Li et al, 2005), and their phylogeny is distant enough to make them susceptible to different ligands (Moore et al, 2006). An ancillary benefit is that assay protocols and reagents used for both assays were nearly identical; the major difference is the transient transfection procedure for each receptor's particular ligand binding domain.…”

Section: Discussionmentioning

confidence: 99%

“…They are involved in diverse biological processes, such as embryogenesis, homeostasis, reproduction, cell growth, and death (Mangelsdorf et al, 1995). With numerous NR-targeting drugs marketed or in development, NRs have proven to be successful therapeutic targets for a wide range of diseases (Moore et al, 2006). Whereas natural or synthetic ligands have been reported for numerous members of the NR superfamily, the pharmacology of so-called "orphan" nuclear receptors-for which no natural ligand has been reported-as well as those recently "adopted" remains poorly characterized (Giguère, 1999).…”

mentioning

confidence: 99%

Potent, Selective and Cell Penetrant Inhibitors of SF-1 by Functional Ultra-High-Throughput Screening

Madoux

Li²,

Chase³

et al. 2008

Mol Pharmacol

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The steroidogenic factor 1 (SF-1, also known as NR5A1) is a transcription factor belonging to the nuclear receptor superfamily. Whereas most of the members of this family have been extensively characterized, the therapeutic potential and pharmacology of SF-1 still remains elusive. Described here is the identification and characterization of selective inhibitory chemical probes of SF-1 by a rational ultra-high-throughput screening ( Their cytotoxicity, solubility, permeability and metabolic stability were also measured. These isoquinolinones represent valuable chemical probes to investigate the therapeutic potential of SF-1.

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The Nuclear Receptor Superfamily and Drug Discovery

Cited by 13 publications

References 124 publications

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

RORs in Autoimmune Disease

Potent, Selective and Cell Penetrant Inhibitors of SF-1 by Functional Ultra-High-Throughput Screening

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