The nuclear receptors are a superfamily of ligand-activated transcription regulators that control many important cellular processes in humans. These soluble, intracellular proteins are modular constructs that contain a C-terminal ligand binding domain (LBD), a central DNA binding domain (DBD), and an N-terminal transcriptional transactivation domain (AF-1). The ligands that activate these receptors by binding to the LBD are lipophilic small-molecule hormones such as steroids, retinoids, and thyroid hormone. The nuclear receptor superfamily is arguably the most important class of biomedical targets presently known; drugs that target nuclear receptors are either currently used or under development for a wide range of indications including inflammation, hypertension, osteoporosis, hypercholestermia, diabetes, and various cancers. Important progress made over the past few years in structural and cell biology has led to a basic understanding of some of the bioregulatory mechanisms of nuclear receptors. The field is now at a critical point where the tools of organic chemistry can be used to reveal the detailed mechanistic underpinnings of how this important class of transcriptional regulatory proteins work. The research described in this proposal uses a chemistry-based approach to address two central questions concerning nuclear receptor transcriptional regulation: 1) ow do agonist ligands turn receptors on and how do antagonist ligands turn receptors off?; and 2) what are the molecular origins of the tissue-specific actions of nuclear receptor ligands? Three different nuclear receptors will be studied in the research plan.
In Aim 1, the thyroid receptor will be used as a model to test a general structure-based hypothesis for nuclear receptor antagonist design.
In Aim 2, the estrogen receptor will be used to examine a family of non-steroidal agonist and antagonist ligands structurally related to tamoxifen and reloxifene which are drugs that show tissue-specific estrogen receptor actions.
In Aim 3, the receptor will be used in the development of non-steroidal ligands that are selective for specific glucocorticoid response elements. These ligand-based studies could provide key insight into the bioregulatory mechanisms of nuclear receptor function, and could provide new insight into the design of safer and more effective therapeutics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Margolis, Ronald N
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University of California San Francisco
Schools of Pharmacy
San Francisco
United States
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Ferrara, Skylar J; Bourdette, Dennis; Scanlan, Thomas S (2018) Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics. Endocrinology 159:2733-2740
Bárez-López, Soledad; Hartley, Meredith D; Grijota-Martínez, Carmen et al. (2018) Sobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain. Thyroid 28:1211-1220
Devereaux, Jordan; Ferrara, Skylar J; Scanlan, Thomas S (2018) Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples. Methods Mol Biol 1801:193-206
Aguayo-Mazzucato, Cristina; Lee Jr, Terence B; Matzko, Michelle et al. (2018) T3 Induces Both Markers of Maturation and Aging in Pancreatic ?-Cells. Diabetes 67:1322-1331
Yu, Guoying; Tzouvelekis, Argyris; Wang, Rong et al. (2018) Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24:39-49
Meinig, J Matthew; Ferrara, Skylar J; Banerji, Tania et al. (2017) Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy. ACS Chem Neurosci 8:2468-2476
Ma, Hongwei; Yang, Fan; Butler, Michael R et al. (2017) Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 31:3425-3438
Hartley, Meredith D; Kirkemo, Lisa L; Banerji, Tapasree et al. (2017) A Thyroid Hormone-Based Strategy for Correcting the Biochemical Abnormality in X-Linked Adrenoleukodystrophy. Endocrinology 158:1328-1338
Ferrara, Skylar J; Meinig, J Matthew; Placzek, Andrew T et al. (2017) Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorg Med Chem 25:2743-2753
Placzek, Andrew T; Ferrara, Skylar J; Hartley, Meredith D et al. (2016) Sobetirome prodrug esters with enhanced blood-brain barrier permeability. Bioorg Med Chem 24:5842-5854

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