Format

Send to

Choose Destination
J Pharmacol Exp Ther. 2015 Mar;352(3):579-89. doi: 10.1124/jpet.114.221150. Epub 2015 Jan 9.

Efficacy and mechanism of action of volasertib, a potent and selective inhibitor of Polo-like kinases, in preclinical models of acute myeloid leukemia.

Author information

1
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.) dorothea.rudolph@boehringer-ingelheim.com.
2
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.).

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.

PMID:
25576074
DOI:
10.1124/jpet.114.221150
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center