Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Germany.
Bioorg Med Chem. 2011 Jun 15;19(12):3717-31. doi: 10.1016/j.bmc.2011.02.032. Epub 2011 Feb 27.
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.
精氨酸甲基化是一种表观遗传修饰，由于其在多种疾病中发挥着重要作用，因此受到越来越多的关注。对于激素依赖性癌症来说尤其如此，因为精氨酸甲基转移酶 I（PRMT1）介导的组蛋白甲基化参与了性激素受体的激活。因此，PRMT 抑制剂是潜在的药物，也是细胞生物学的有趣工具。我们小组之前发现的一种达普松衍生物——别嘌呤达普松，可用作抑制剂合成的先导结构。体外试验表明，对氨基苯磺酰胺的酰化衍生物和抗麻风病药物达普松是 PRMT1 的新型抑制剂。与精氨酸甲基转移酶 CARM1 和赖氨酸甲基转移酶 Set7/9 相比，达普松的双氯乙酰酰胺对人 PRMT1 的抑制作用具有选择性，在低微摩尔区域选择性抑制 PRMT1。它在 MCF7a 和 LNCaP 细胞上表现出抗癌活性，并在报告基因系统中特异性阻断雄激素依赖性转录。同样，在 LNCaP 细胞中，使用定量 RT-PCR 对雄激素依赖性基因的 mRNA 进行检测，也证明了转录阻断。
