Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites
| Autor: | Ed E. Moret, Nathaniel I. Martin, Matthijs J. van Haren, Linda Quarles van Ufford |
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| Rok vydání: | 2015 |
| Předmět: |
Protein-Arginine N-Methyltransferases
Spectrometry Mass Electrospray Ionization Binding Sites Magnetic Resonance Spectroscopy Methyltransferase Arginine biology Organic Chemistry Methylation Biochemistry Small molecule chemistry.chemical_compound Histone chemistry biology.protein Enzyme Inhibitors Physical and Theoretical Chemistry Binding site Guanidine |
| Zdroj: | Organic & Biomolecular Chemistry. 13:549-560 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c4ob01734j |
| Popis: | The protein arginine N-methyltransferases (PRMTs) are a family of enzymes that function by specifically transferring a methyl group from the cofactor S-adenosyl-L-methionine (AdoMet) to the guanidine group of arginine residues in target proteins. The most notable is the PRMT-mediated methylation of arginine residues that are present in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases including various forms of cancer. The development of PRMT inhibitors may therefore hold potential as a means of developing new therapeutics. We here report the synthesis and evaluation of a series of small molecule PRMT inhibitors designed to simultaneously occupy the binding sites of both the guanidino substrate and AdoMet cofactor. Potent inhibition and surprising selectivity were observed when testing these compounds against a panel of methyltransferases. |
| Databáze: | OpenAIRE |
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