Discovery of a First-in-Class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor.
J Med Chem
; 63(10): 5477-5487, 2020 05 28.
Article
em En
| MEDLINE
| ID: mdl-32367723
ABSTRACT
Protein arginine methyltransferase 6 (PRMT6) plays important roles in several biological processes associated with multiple cancers. Well-characterized potent, selective, and cell-active PRMT6 inhibitors are invaluable tools for testing biological and therapeutic hypotheses. Although there are several known reversible PRMT6 inhibitors, covalent PRMT6 inhibitors have not been reported. Based on a cocrystal structure of PRMT6-MS023 (a type I PRMT inhibitor), we discovered the first potent and cell-active irreversible PRMT6 inhibitor, 4 (MS117). The covalent binding mode of compound 4 to PRMT6 was confirmed by mass spectrometry and kinetic studies and by a cocrystal structure. Compound 4 did not covalently modify other closely related PRMTs, potently inhibited PRMT6 in cells, and was selective for PRMT6 over other methyltransferases. We also developed two structurally similar control compounds, 5 (MS167) and 7 (MS168). We provide these valuable chemical tools to the scientific community for further studying PRMT6 physiological and pathophysiological functions.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína-Arginina N-Metiltransferases
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Proteínas Nucleares
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Inibidores Enzimáticos
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Descoberta de Drogas
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article