A novel arginine methyltransferase inhibitor with cellular activity

A new cell permeable arginine methyltransferase inhibitor by fragment based virtual screening is reported. Via virtual screening we identified a thioglycolic amide as an arginine methyltransferase (PRMT) inhibitor and tested it and related compounds against the fungal PRMT RmtA and human PRMT1. Comp...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-08, Vol.17 (15), p.4150-4153
Hauptverfasser:	Spannhoff, Astrid, Machmur, Rospita, Heinke, Ralf, Trojer, Patrick, Bauer, Ingo, Brosch, Gerald, Schüle, Roland, Hanefeld, Wolfgang, Sippl, Wolfgang, Jung, Manfred
Format:	Artikel
Sprache:	eng
Schlagworte:	Amides - chemistry Amides - pharmacology Antineoplastic agents Arginine methyltransferase Biological and medical sciences Cell Line Chromatin Docking Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General aspects Histone methyltransferase Humans Intracellular Signaling Peptides and Proteins Medical sciences Methyltransferases - antagonists & inhibitors Models, Molecular Pharmacology. Drug treatments PRMT Protein-Arginine N-Methyltransferases Virtual screening
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Beschreibung
Zusammenfassung:	A new cell permeable arginine methyltransferase inhibitor by fragment based virtual screening is reported. Via virtual screening we identified a thioglycolic amide as an arginine methyltransferase (PRMT) inhibitor and tested it and related compounds against the fungal PRMT RmtA and human PRMT1. Compound RM65 was the most potent druglike inhibitor (IC 50-PRMT1: 55.4 μM) and showed histone hypomethylation in HepG2 cells. Docking studies proposed binding at the substrate and SAM cofactor binding pocket. It may serve as a lead for further PRMT inhibitors useful for the treatment for hormone dependent cancers.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.05.088