RESUMO
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.
Assuntos
Arginina/metabolismo , Inibidores Enzimáticos/síntese química , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/metabolismo , S-Adenosilmetionina/metabolismo , Arginina/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Escherichia coli , Humanos , Metilação , Modelos Moleculares , Peso Molecular , Plasmídeos , Ligação Proteica , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/química , Proteína-Arginina N-Metiltransferases/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/química , Proteínas Repressoras/genética , S-Adenosilmetionina/antagonistas & inibidores , Especificidade por Substrato , Transformação BacterianaRESUMO
Prototype inhibitors of protein arginine methyltransferases (PRMTs) have been constructed by attaching guanidine functionality via a variable linker to non-reactive amine analogues of the cellular co-factor (S)-adenosyl methionine (AdoMet). Potent inhibition of PRMT1 (IC(50) of approximately 3-6 microM) combined with weak inhibition of the lysine methyltransferase SET7 (approximately 50% of activity at 100 microM) was observed for two such compounds.
Assuntos
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Concentração Inibidora 50 , Metilação , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Especificidade por SubstratoRESUMO
[reaction: see text]. Cyclic amines may be prepared via a sequence of deprotection followed by intramolecular reductive amination of t-Boc-protected amino ketones under asymmetric transfer hydrogenation conditions. In cases where the corresponding imine reaction proceeds with high enantioselectivity, this is reflected in the one-step process.