Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1.
Org Biomol Chem
; 9(22): 7814-21, 2011 Oct 26.
Article
en En
| MEDLINE
| ID: mdl-21952734
ABSTRACT
Protein arginine N-methyltransferases (PRMTs) selectively replace N-H for N-CH(3) at substrate protein guanidines, a post-translational modification important for a range of biological processes, such as epigenetic regulation, signal transduction and cancer progression. Selective chemical probes are required to establish the dynamic function of individual PRMTs. Herein, model inhibitors designed to occupy PRMT binding sites for an arginine substrate and S-adenosylmethionine (AdoMet) co-factor are described. Expedient access to such compounds by modular synthesis is detailed. Remarkably, biological evaluation revealed some compounds to be potent inhibitors of PRMT1, but inactive against CARM1. Docking studies show how prototype compounds may occupy the binding sites for a co-factor and arginine substrate. Overlay of PRMT1 and CARM1 binding sites suggest a difference in a single amino acid that may be responsible for the observed selectivity.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Arginina
/
Proteína-Arginina N-Metiltransferasas
/
Proteínas Represoras
/
S-Adenosilmetionina
/
Proteínas Recombinantes de Fusión
/
Procesamiento Proteico-Postraduccional
/
Inhibidores Enzimáticos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Org Biomol Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2011
Tipo del documento:
Article