Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases.
Future Med Chem
; 8(13): 1553-71, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-26971619
ABSTRACT
BACKGROUND:
Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition. METHODS &RESULTS:
Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3.CONCLUSION:
Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Pró-Fármacos
/
Histona Desmetilases com o Domínio Jumonji
/
Inibidores de Histona Desacetilases
/
Ácidos Isonicotínicos
Limite:
Humans
Idioma:
En
Revista:
Future Med Chem
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Alemanha