Department of Chemistry, Program of Molecular Basis of Diseases, Georgia State University, P.O. Box 4098, Atlanta, Georgia 30302, USA.
J Med Chem. 2012 Sep 27;55(18):7978-87. doi: 10.1021/jm300521m. Epub 2012 Sep 12.
Protein arginine methyltransferases (PRMTs) are proved to play vital roles in chromatin remodeling, RNA metabolism, and signal transduction. Aberrant regulation of PRMT activity is associated with various pathological states such as cancer and cardiovascular disorders. Development and application of small molecule PRMT inhibitors will provide new avenues for therapeutic discovery. The combination of pharmacophore-based virtual screening methods with radioactive methylation assays provided six hits identified as inhibitors against the predominant arginine methyltransferase PRMT1 within micromolar potency. Two potent compounds, A9 and A36, exhibited the inhibitory effect by directly targeting substrate H4 other than PRMT1 and displayed even higher inhibition activity than the well-known PRMT inhibitors AMI-1. A9 significantly inhibits proliferation of castrate-resistant prostate cancer cells. Together, A9 may be a potential inhibitor against advanced hormone-independent cancers, and the work will provide clues for the future development of specific compounds that block the interaction of PRMTs with their targets.
精氨酸甲基转移酶（PRMTs）在染色质重塑、RNA 代谢和信号转导中起着重要作用。PRMT 活性的异常调节与癌症和心血管疾病等各种病理状态有关。开发和应用小分子 PRMT 抑制剂将为治疗发现提供新途径。基于药效团的虚拟筛选方法与放射性甲基化测定相结合，确定了 6 个作为抑制剂的命中物，其对主要的精氨酸甲基转移酶 PRMT1 的活性具有微摩尔效力。两种有效的化合物 A9 和 A36 通过直接靶向除 PRMT1 以外的底物 H4 发挥抑制作用，其抑制活性甚至高于著名的 PRMT 抑制剂 AMI-1。A9 显著抑制去势抵抗性前列腺癌细胞的增殖。总之，A9 可能是一种针对晚期激素非依赖性癌症的潜在抑制剂，该工作将为未来开发特异性阻断 PRMTs 与其靶标的相互作用的化合物提供线索。
