Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
12 10 2023
12 10 2023
Historique:
medline:
23
10
2023
pubmed:
10
8
2023
entrez:
10
8
2023
Statut:
ppublish
Résumé
Less studied than the other protein arginine methyltransferase isoforms, PRMT7 and PRMT9 have recently been identified as important therapeutic targets. Yet, most of their biological roles and functions are still to be defined, as well as the structural requirements that could drive the identification of selective modulators of their activity. We recently described the structural requirements that led to the identification of potent and selective PRMT4 inhibitors spanning both the substrate and the cosubstrate pockets. The reanalysis of the data suggested a PRMT7 preferential binding for shorter derivatives and prompted us to extend these structural studies to PRMT9. Here, we report the identification of the first potent PRMT7/9 inhibitor and its binding mode to the two PRMT enzymes. Label-free quantification mass spectrometry confirmed significant inhibition of PRMT activity in cells. We also report the setup of an effective AlphaLISA assay to screen small molecule inhibitors of PRMT9.
Identifiants
pubmed: 37560786
doi: 10.1021/acs.jmedchem.3c01030
pmc: PMC10578352
doi:
Substances chimiques
Arginine
94ZLA3W45F
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
PRMT7 protein, human
EC 2.1.1.319
FBXO11 protein, human
EC 2.1.1.319
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
13665-13683Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM133850
Pays : United States
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