Click chemistry enables preclinical evaluation of targeted epigenetic therapies.
Science
; 356(6345): 1397-1401, 2017 06 30.
Article
en En
| MEDLINE
| ID: mdl-28619718
ABSTRACT
The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Benzodiazepinas
/
Leucemia
/
Sistemas de Liberación de Medicamentos
/
Química Clic
/
Epigenómica
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Science
Año:
2017
Tipo del documento:
Article
País de afiliación:
Australia