Novel therapeutic candidates, identified by molecular modeling, induce γ-globin gene expression in vivo.
Blood Cells Mol Dis
; 47(2): 107-16, 2011 Aug 15.
Article
en En
| MEDLINE
| ID: mdl-21641240
ABSTRACT
The ß-hemoglobinopathies and thalassemias are serious genetic blood disorders affecting the ß-globin chain of hemoglobin A (α(2)ß(Α)(2)). Their clinical severity can be reduced by enhancing expression of fetal hemoglobin (γ-globin), producing HbF (α(2)γ(2,)). In studies reported here, γ-globin induction by 23 novel, structurally-unrelated compounds, which had been predicted through molecular modeling and in silico screening of a 13,000 chemical library, was evaluated in vitro in erythroid progenitors cultured from normal subjects and ß-thalassemia patients, and in vivo in transgenic mice or anemic baboons. Four predicted candidates were found to have high potency, with 4- to 8-fold induction of HbF. Two of these compounds have pharmacokinetic profiles favorable for clinical application. These studies thus effectively identified high potency γ-globin inducing candidate therapeutics and validated the utility of in silico molecular modeling.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Productos Biológicos
/
Hemoglobina Fetal
/
Diseño de Fármacos
/
Células Precursoras Eritroides
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Talasemia beta
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Bibliotecas de Moléculas Pequeñas
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Gamma-Globinas
/
Anemia
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Blood Cells Mol Dis
Asunto de la revista:
HEMATOLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos