期刊
BIOMOLECULES
卷 11, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/biom11060854
关键词
protein arginine methyltransferases; inhibitor; methyltransferase; competitive inhibitor
资金
- Department of Medicinal Chemistry and Molecular Pharmacology (RH) at Purdue University, West Lafayette, IN, USA
In this study, a potent pan-inhibitor II757 for PRMTs was designed and synthesized, showing high inhibition for various PRMTs and competitively binding at the SAM binding site of PRMT1. II757 also exhibited selectivity for PRMTs over other methyltransferases, serving as a general probe and a lead for further optimization.
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 (IC50) value of 5 to 555 nM for eight tested PRMTs, with the highest inhibition for PRMT4 (IC50 = 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.
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