Arginine methylation is a common posttranslational modification that can regulate protein function. The main pool of proteins that are arginine methylated possess RNA binding properties. In addition, enzymes that facilitate histone acetylation (CBP/p300) and histones themselves are arginine methylated - thus implicating this posttranslational modification in chromatin remodeling and transcriptional regulation. Seven protein arginine N-methyltransferases (PRMTs) have been identified in mammalian cells: PRMT1, PRMT2, PRMTS, PRMT4/CARM1, PRMT5/JBP1, PRMT6 and PRMT7. Using a chemical library and in vitro experimental approaches, we propose to develop pilot screens to identify small molecules that will perturb arginine methylation in mammalian cells. The screens will be developed in such a way that they can be automated for subsequent high throughput chemical screening (HTS) by the planned NIH-funded HTS screening centers. The PRMTs are novel drug targets that regulate protein interactions and transcription/translation. Thus, the identification of small molecule regulators of arginine methylation will provide lead compounds for future drug development, targeting cancer and possibly other disease states. Most importantly, the PRMTs are a newly identified family of enzymes that have not yet been tapped as """"""""drugable"""""""" targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114116-03
Application #
7207995
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Song, Min-Kyung H
Project Start
2005-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$215,478
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Mai, Antonello; Valente, Sergio; Cheng, Donghang et al. (2007) Synthesis and biological validation of novel synthetic histone/protein methyltransferase inhibitors. ChemMedChem 2:987-91