title: Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitors of the arginine methyltransferase hPRMT1.
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: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Germany.
authors: Elisabeth-Maria
authors: EM
authors: Bissinger
authors: Ralf
authors: R
authors: Heinke
authors: Astrid
authors: A
authors: Spannhoff
authors: Adrien
authors: A
authors: Eberlin
authors: Eric
authors: E
authors: Metzger
authors: Vincent
authors: V
authors: Cura
authors: Pierre
authors: P
authors: Hassenboehler
authors: Jean
authors: J
authors: Cavarelli
authors: Roland
authors: R
authors: Schüle
authors: Mark T
authors: MT
authors: Bedford
authors: Wolfgang
authors: W
authors: Sippl
authors: Manfred
authors: M
authors: Jung
mesh_terms: D000215:Acylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003622:Dapsone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011484:Protein-Arginine N-Methyltransferases; D011944:Receptors, Androgen / Q000235:genetics; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011944:Receptors, Androgen; D013449:Sulfonamides; D003622:Dapsone; D008780:Methyltransferases; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases