A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFß in leukemic cells.
Leuk Lymphoma
; 59(9): 2188-2200, 2018 09.
Article
en En
| MEDLINE
| ID: mdl-29249175
ABSTRACT
The core binding factor (CBF) gene RUNX1 is a target of chromosomal translocations in leukemia, including t(8;21) in acute myeloid leukemia (AML). Normal CBF function is essential for activity of AML1-ETO, product of the t(8;21), and for survival of several leukemias lacking RUNX1 mutations. Using virtual screening and optimization, we developed Runt domain inhibitors which bind to the Runt domain and disrupt its interaction with CBFß. On-target activity was demonstrated by the Runt domain inhibitors' ability to depress hematopoietic cell formation in zebrafish embryos, reduce growth and induce apoptosis of t(8;21) AML cell lines, and reduce progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells. Runt domain inhibitors had similar effects on murine and human T cell acute lymphocytic leukemia (T-ALL) cell lines. Our results confirmed that Runt domain inhibitors might prove efficacious in various AMLs and in T-ALL.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Subunidades alfa del Factor de Unión al Sitio Principal
/
Subunidad beta del Factor de Unión al Sitio Principal
/
Bibliotecas de Moléculas Pequeñas
/
Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Leuk Lymphoma
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos