The broad, long-term objectives of this proposal are the development of novel inhibitors that specifically prevent the interaction of nuclear receptors with their coactivating proteins through their NR box binding site and thus functionally block transcriptional activation by nuclear receptors.
The Specific Aims of this proposal are 1) To use conformationally constrained peptide inhibitors of the interaction of the human thyroid receptor (hTRf3 1) with the glucocorticoid receptor interacting protein 1 (GRIP 1) to evaluate the structure-activity relationships of the individual leucine side chains of the LXXLL triad (NR box) of GRIP 1; 2) to design and synthesize sets of non-peptide compounds that mimic the side chain presentation of the LXXLL triad in order to establish viable scaffolds for discovery library synthesis that present their side chains in the correct geometry; 3) to synthesize libraries of non-peptide inhibitors and screen these to find specific inhibitors for nuclear receptor coactivator interactions; 4) to expand the biochemical model systems under consideration to include the estrogen receptor (ER), androgen receptor (AR), and peroxisome proliferator-activated receptor (PPAR) thus allowing the study of the specificity of inhibition of the nuclear receptor coactivator interactions; and 5) to optimize any active inhibitors of nuclear receptor function for maximal potency against particular receptors and selectivity among receptors. 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 cancer, cardiovascular disease, diabetes, and osteoporosis - diseases currently treated with drugs based upon hormone structure. The research design is the use of molecular design and combinatorial chemistry to develop non-peptide inhibitors. The methods to be used are chemical synthesis, biochemical screening, structure determination, molecular design, and cellular biology evaluation of physiological effect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058080-03
Application #
6619842
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Margolis, Ronald N
Project Start
2001-09-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$294,337
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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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