A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes

• Published in: Biomolecules (Basel, Switzerland) Vol. 11; no. 6; p. 854
• Main Authors: Iyamu, Iredia D, Al-Hamashi, Ayad A, Huang, Rong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.06.2021; MDPI
• Subjects: Amino acids; Binding sites; Competition; competitive inhibitor; DNA damage; DNA repair; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzymes; Humans; inhibitor; Investigations; methyltransferase; Peptides; Protein arginine methyltransferase; protein arginine methyltransferases; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - chemistry; Proteins; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - chemistry; Signal transduction; Transcription; competitive inhibitor; methyltransferase; inhibitor; protein arginine methyltransferases
• ISSN: 2218-273X; 2218-273X
• 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.