Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitors of the arginine methyltransferase hPRMT1

• Published in: Bioorganic & medicinal chemistry 2011-06, Vol.19 (12), p.3717-3731
• Main Authors: Bissinger, Elisabeth-Maria, Heinke, Ralf, Spannhoff, Astrid, Eberlin, Adrien, Metzger, Eric, Cura, Vincent, Hassenboehler, Pierre, Cavarelli, Jean, Schüle, Roland, Bedford, Mark T., Sippl, Wolfgang, Jung, Manfred
• Format: Article
• Language: English
• Subjects: Acylation - drug effects; Allantodapsone; Androgen; anticarcinogenic activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; arginine; Arginine methyltransferase; Biochemistry, Molecular Biology; Cancer; cell biology; Cell Line, Tumor; dapsone; Dapsone - chemical synthesis; Dapsone - chemistry; Dapsone - pharmacology; drugs; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; epigenetics; Gene Expression Regulation, Neoplastic - drug effects; histones; hormone receptors; Humans; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins; Life Sciences; lysine; messenger RNA; methylation; Methyltransferases - antagonists & inhibitors; Models, Molecular; Molecular Structure; PRMT1; Protein-Arginine N-Methyltransferases; Receptors, Androgen - genetics; reporter genes; reverse transcriptase polymerase chain reaction; S-Adenosylmethionine; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; transcription (genetics)
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2011.02.032

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.