The broad, long-term objectives of this proposal are the development of novel """"""""drug-like"""""""" inhibitors that specifically prevent the interaction of nuclear receptors with their coregulating proteins through their NR box binding site and functionally block transcriptional activation by nuclear receptors.
The Specific Aims of this proposal are 1) to determine which chemical scaffolds can afford small molecule inhibitors of the interaction of co-regulators with the thyroid receptor (TR), glucocorticoid receptor (GR), androgen receptor (AR) and peroxisome proliferator activated receptor y (PPARy) and which scaffolds exhibit selectivity for individual receptors; 2) to understand the molecular mechanism of inhibitor function by determining the modes of binding of active inhibitors and the structure activity relationships of scaffolds with individual receptors and among receptors; and 3) to determine how molecular selectivity of action against a particular receptor relates to functional changes in signaling by the targeted receptor and overall changes in transcriptional regulation in the cellular environment. The health relatedness of this project is that the new method of inhibiting nuclear receptor function has the potential to provide new therapies for diseases mediated by nuclear receptors which include cardiovascular disease, diabetes, and osteoporosis - diseases currently treated with drugs based upon hormone structure. The research design is the use of knowledge based structure, chemistry, and cell biology to rationally produce novel small molecule inhibitors of the targeted protein interaction. The methods to be used are high throughput screening, parallel chemistry, medicinal chemistry, high throughput X-ray crystallography (structural genomics), cell biology, genomics, and pharmacology to develop inhibitors.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Margolis, Ronald N
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St. Jude Children's Research Hospital
United States
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Hwang, Jong Yeon; Attia, Ramy R; Carrillo, Angela K et al. (2013) Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction. Bioorg Med Chem Lett 23:1891-5
Nandhikonda, Premchendar; Lynt, Wen Z; McCallum, Megan M et al. (2012) Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators. J Med Chem 55:4640-51
Hwang, Jong Yeon; Attia, Ramy R; Zhu, Fangyi et al. (2012) Synthesis and evaluation of sulfonylnitrophenylthiazoles (SNPTs) as thyroid hormone receptor-coactivator interaction inhibitors. J Med Chem 55:2301-10
Lack, Nathan A; Axerio-Cilies, Peter; Tavassoli, Peyman et al. (2011) Targeting the binding function 3 (BF3) site of the human androgen receptor through virtual screening. J Med Chem 54:8563-73
Hwang, Jong Yeon; Huang, Wenwei; Arnold, Leggy A et al. (2011) Methylsulfonylnitrobenzoates, a new class of irreversible inhibitors of the interaction of the thyroid hormone receptor and its obligate coactivators that functionally antagonizes thyroid hormone. J Biol Chem 286:11895-908
Feau, Clementine; Arnold, Leggy A; Kosinski, Aaron et al. (2011) Ligand competition binding assay for the androgen receptor. Methods Mol Biol 776:59-68
Johnson, Ronald L; Hwang, Jong Yeon; Arnold, Leggy A et al. (2011) A quantitative high-throughput screen identifies novel inhibitors of the interaction of thyroid receptor beta with a peptide of steroid receptor coactivator 2. J Biomol Screen 16:618-27
De Leon, Johanny Tonos; Iwai, Aki; Feau, Clementine et al. (2011) Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proc Natl Acad Sci U S A 108:11878-83
Sadana, Prabodh; Hwang, Jong Yeon; Attia, Ramy R et al. (2011) Similarities and differences between two modes of antagonism of the thyroid hormone receptor. ACS Chem Biol 6:1096-106
Féau, Clémentine; Arnold, Leggy A; Kosinski, Aaron et al. (2009) Novel flufenamic acid analogues as inhibitors of androgen receptor mediated transcription. ACS Chem Biol 4:834-43

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