Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
Science
; 340(6132): 622-6, 2013 May 03.
Article
em En
| MEDLINE
| ID: mdl-23558173
ABSTRACT
A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Compostos de Fenilureia
/
Sulfonamidas
/
Leucemia Mieloide Aguda
/
Inibidores Enzimáticos
/
Hematopoese
/
Isocitrato Desidrogenase
Idioma:
En
Revista:
Science
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos