Abstract |
Arginine methylation is an epigenetic modification that receives increasing interest as it plays an important role in several diseases. This is especially true for hormone-dependent cancer, seeing that histone methylation by arginine methyltransferase I (PRMT1) is involved in the activation of sexual hormone receptors. Therefore, PRMT inhibitors are potential drugs and interesting tools for cell biology. A dapsone derivative called allantodapsone previously identified by our group served as a lead structure for inhibitor synthesis. Acylated derivatives of p-aminobenzenesulfonamides and the antilepra drug dapsone were identified as new inhibitors of PRMT1 by in vitro testing. The bis-chloroacetyl amide of dapsone selectively inhibited human PRMT1 in the low micromolar region and was selective for PRMT1 as compared to the arginine methyltransferase CARM1 and the lysine methyltransferase Set7/9. It showed anticancer activity on MCF7a and LNCaP cells and blocked androgen dependent transcription specifically in a reporter gene system. Likewise, a transcriptional block was also demonstrated in LNCaP cells using quantitative RT-PCR on the mRNA of androgen dependent genes.
|
Authors | Elisabeth-Maria Bissinger, Ralf Heinke, Astrid Spannhoff, Adrien Eberlin, Eric Metzger, Vincent Cura, Pierre Hassenboehler, Jean Cavarelli, Roland Schüle, Mark T Bedford, Wolfgang Sippl, Manfred Jung |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 19
Issue 12
Pg. 3717-31
(Jun 15 2011)
ISSN: 1464-3391 [Electronic] England |
PMID | 21440447
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Enzyme Inhibitors
- Intracellular Signaling Peptides and Proteins
- Receptors, Androgen
- Sulfonamides
- Dapsone
- Methyltransferases
- PRMT2 protein, human
- Protein-Arginine N-Methyltransferases
|
Topics |
- Acylation
(drug effects)
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Cell Line, Tumor
- Dapsone
(chemical synthesis, chemistry, pharmacology)
- Enzyme Inhibitors
(chemical synthesis, chemistry, pharmacology)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Inhibitory Concentration 50
- Intracellular Signaling Peptides and Proteins
- Methyltransferases
(antagonists & inhibitors)
- Models, Molecular
- Molecular Structure
- Protein-Arginine N-Methyltransferases
- Receptors, Androgen
(genetics)
- Sulfonamides
(chemical synthesis, chemistry, pharmacology)
|