Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
11 Jul 2019
11 Jul 2019
Historique:
received:
26
02
2019
accepted:
22
05
2019
entrez:
18
7
2019
pubmed:
18
7
2019
medline:
18
7
2019
Statut:
epublish
Résumé
Protein arginine methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 possesses a cysteine (C449) in the active site, unique to PRMT5. Therefore, covalent PRMT5 inhibition is an attractive chemical approach. Herein, we report an exciting discovery of a series of novel hemiaminals that under physiological conditions can be converted to aldehydes and react with C449 to form covalent adducts, which presumably undergo an unprecedented elimination to form the thiol-vinyl ethers, as indicated by electron density in the co-crystal structure of the PRMT5/MEP50 complex.
Identifiants
pubmed: 31312404
doi: 10.1021/acsmedchemlett.9b00074
pmc: PMC6627734
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1033-1038Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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