Iyamu Iredia D, Al-Hamashi Ayad A, Huang Rong
Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bab-almoadham, Baghdad 10047, Iraq.
Biomolecules. 2021 Jun 8;11(6):854. doi: 10.3390/biom11060854.
Protein arginine methyltransferases (PRMTs) play important roles in transcription, splicing, DNA damage repair, RNA biology, and cellular metabolism. Thus, PRMTs have been attractive targets for various diseases. In this study, we reported the design and synthesis of a potent pan-inhibitor for PRMTs that tethers a thioadenosine and various substituted guanidino groups through a propyl linker. Compound II757 exhibits a half-maximal inhibition concentration (IC) value of 5 to 555 nM for eight tested PRMTs, with the highest inhibition for PRMT4 (IC = 5 nM). The kinetic study demonstrated that II757 competitively binds at the SAM binding site of PRMT1. Notably, II757 is selective for PRMTs over a panel of other methyltransferases, which can serve as a general probe for PRMTs and a lead for further optimization to increase the selectivity for individual PRMT.
蛋白质精氨酸甲基转移酶（PRMTs）在转录、剪接、DNA损伤修复、RNA生物学和细胞代谢中发挥着重要作用。因此，PRMTs一直是各种疾病颇具吸引力的靶点。在本研究中，我们报道了一种强效PRMTs泛抑制剂的设计与合成，该抑制剂通过丙基连接子连接硫代腺苷和各种取代胍基。化合物II757对8种受试PRMTs的半数最大抑制浓度（IC）值为5至555 nM，对PRMT4的抑制作用最强（IC = 5 nM）。动力学研究表明，II757在PRMT1的SAM结合位点竞争性结合。值得注意的是，与其他一组甲基转移酶相比，II757对PRMTs具有选择性，可作为PRMTs的通用探针以及进一步优化以提高对单个PRMT选择性的先导化合物。
