Efficacy and mechanism of action of volasertib, a potent and selective inhibitor of Polo-like kinases, in preclinical models of acute myeloid leukemia.
J Pharmacol Exp Ther
; 352(3): 579-89, 2015 Mar.
Article
em En
| MEDLINE
| ID: mdl-25576074
ABSTRACT
Polo-like kinase 1 (Plk1), a member of the Polo-like kinase family of serine/threonine kinases, is a key regulator of multiple steps in mitosis. Here we report on the pharmacological profile of volasertib, a potent and selective Plk inhibitor, in multiple preclinical models of acute myeloid leukemia (AML) including established cell lines, bone marrow samples from AML patients in short-term culture, and subcutaneous as well as disseminated in vivo models in immune-deficient mice. Our results indicate that volasertib is highly efficacious as a single agent and in combination with established and emerging AML drugs, including the antimetabolite cytarabine, hypomethylating agents (decitabine, azacitidine), and quizartinib, a signal transduction inhibitor targeting FLT3. Collectively, these preclinical data support the use of volasertib as a new therapeutic approach for the treatment of AML patients, and provide a foundation for combination approaches that may further improve and prolong clinical responses.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pteridinas
/
Leucemia Mieloide Aguda
/
Proteínas Proto-Oncogênicas
/
Proteínas Serina-Treonina Quinases
/
Proteínas de Ciclo Celular
/
Inibidores de Proteínas Quinases
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Pharmacol Exp Ther
Ano de publicação:
2015
Tipo de documento:
Article