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J Med Chem. 2010 Aug 26;53(16):6028-39. doi: 10.1021/jm100416n.

Discovery and mechanistic study of a class of protein arginine methylation inhibitors.

Author information

1
Department of Chemistry, Center for Biotechnology and Drug Design, Georgia State University, P.O. Box 4098, Atlanta, Georgia 30302, USA.

Abstract

Protein arginine methylation regulates multiple biological processes such as chromatin remodeling and RNA splicing. Malfunction of protein arginine methyltransferases (PRMTs) is correlated with many human diseases. Thus, small molecule inhibitors of protein arginine methylation are of great potential for therapeutic development. Herein, we report a type of compound that blocks PRMT1-mediated arginine methylation at micromolar potency through a unique mechanism. Most of the discovered compounds bear naphthalene and sulfonate groups and are structurally different from typical PRMT substrates, for example, histone H4 and glycine- and arginine-rich sequences. To elucidate the molecular basis of inhibition, we conducted a variety of kinetic and biophysical assays. The combined data reveal that this type of naphthyl-sulfo (NS) molecule directly targets the substrates but not PRMTs for the observed inhibition. We also found that suramin effectively inhibited PRMT1 activity. These findings about novel PRMT inhibitors and their unique inhibition mechanism provide a new way for chemical regulation of protein arginine methylation.

PMID:
20666457
DOI:
10.1021/jm100416n
[Indexed for MEDLINE]

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