Identification of small-molecule HSF1 amplifiers by high content screening in protection of cells from stress induced injury.
Biochem Biophys Res Commun
; 390(3): 925-30, 2009 Dec 18.
Article
em En
| MEDLINE
| ID: mdl-19852939
ABSTRACT
Small molecule amplifiers of heat shock response have shown promising results in rescuing stress related injury through chaperone amplification. Herein, we report the results of a high content target-based primary screening of several known bioactive libraries. Screening resulted in the identification of three potent gedunin derivatives and a sappanone A derivative. Western blot results confirmed compound-induced activation of HSF1 and increased expression level of HSP70. These compounds rescued cells from cell death caused by proteasome inhibitor MG-132 and RNAi knockdown of HSF1 significantly reversed the cytoprotective effects, confirming an HSF1-dependent mechanism of action. These HSF1 amplifiers were tested in two mammalian cell based models of Huntington's disease (HD) and found to improve survival. Therefore, these screening hits may have therapeutic potential for HD and possibly other protein conformational disorders.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Proteínas de Choque Térmico HSP70
/
Citoproteção
/
Proteínas de Ligação a DNA
/
Bibliotecas de Moléculas Pequenas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos