Diamidine Compounds for Selective Inhibition of Protein Arginine Methyltransferase 1

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• 作者：Leilei Yan ; Chunli Yan ; Kun Qian ; Hairui Su ; Stephanie A. Kofsky-Wofford ; Wei-Chao Lee ; Xinyang Zhao ; Meng-Chiao Ho ; Ivaylo Ivanov ; Yujun George Zheng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2611-2622
• 全文大小：573K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) has been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targeting many methyltransferase enzymes that use S-adenosyl-l-methionine as a cofactor. Here we report diamidine compounds for specific inhibition of PRMT1, the primary type I enzyme. Docking, molecular dynamics, and MM/PBSA analysis together with biochemical assays were conducted to understand the binding modes of these inhibitors and the molecular basis of selective inhibition for PRMT1. Our data suggest that 2,5-bis(4-amidinophenyl)furan (1, furamidine, DB75), one leading inhibitor, targets the enzyme active site and is primarily competitive with the substrate and noncompetitive toward the cofactor. Furthermore, cellular studies revealed that 1 is cell membrane permeable and effectively inhibits intracellular PRMT1 activity and blocks cell proliferation in leukemia cell lines with different genetic lesions.