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J. Biol. Chem., Vol. 279, Issue 23, 23892-23899, June 4, 2004

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Small Molecule Regulators of Protein Arginine Methyltransferases^*

Donghang Cheng, Neelu Yadav, Randall W. King, Maurice S. Swanson¶, Edward J. Weinstein||**, and Mark T. Bedford

From the The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, the Department of Cell Biology, Institute of Chemistry and Cell Biology and the ^||Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and the ^¶Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida 32610-0266

Here we report the identification of small molecules that specifically inhibit protein arginine N-methyltransferase (PRMT) activity. PRMTs are a family of proteins that either monomethylate or dimethylate the guanidino nitrogen atoms of arginine side chains. This common post-translational modification is implicated in protein trafficking, signal transduction, and transcriptional regulation. Most methyltransferases use the methyl donor, S-adenosyl-L-methionine (AdoMet), as a cofactor. Current methyltransferase inhibitors display limited specificity, indiscriminately targeting all enzymes that use AdoMet. In this screen we have identified a primary compound, AMI-1, that specifically inhibits arginine, but not lysine, methyltransferase activity in vitro and does not compete for the AdoMet binding site. Furthermore, AMI-1 prevents in vivo arginine methylation of cellular proteins and can modulate nuclear receptor-regulated transcription from estrogen and androgen response elements, thus operating as a brake on certain hormone actions.

Received for publication, February 19, 2004 , and in revised form, March 30, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Current address: Dept. of Molecular Profiling, Merck & Co., Inc., West Point, PA 19486.

Supported by National Institutes of Health (NIH) Grant DK62248-01, Welch Foundation Grant G-1495, and institutional grants NIEHS, NIH ES07784 and NIH CA16672. To whom correspondence should be addressed: The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, P. O. Box 389, Smithville, TX 78957. Tel.: 512-237-9539; Fax: 512-237-2475; E-mail: mtbedford{at}mdanderson.org.

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