Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors.
Chem Biol Drug Des
; 90(6): 1260-1270, 2017 Dec.
Article
en En
| MEDLINE
| ID: mdl-28636189
ABSTRACT
Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1 inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors. Among them, the most potent compound corresponds to hexamidine (IC50 = 5.9 ± 1.7 µm), which is an antimicrobial agent. The binding between hexamidine and PRMT1 was further validated by thermal shift assays and nuclear magnetic resonance (NMR) experiments. Molecular docking and NMR assays indicated that hexamidine occupied the substrate binding pocket. Furthermore, hexamidine effectively blocked cell proliferation in cancer cell lines related to PRMT1 overexpression. Taken together, this study has provided a druggable scaffold targeting PRMT1 as well as a new way to repurpose old drugs which is a complementary tool for the discovery of new lead compounds.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Proteína-Arginina N-Metiltransferasas
/
Inhibidores Enzimáticos
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Amidas
Límite:
Humans
Idioma:
En
Revista:
Chem Biol Drug Des
Asunto de la revista:
BIOQUIMICA
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FARMACIA
/
FARMACOLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
China