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

Autor:	Rudolph D; 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., Impagnatiello MA; 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.)., Blaukopf C; 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.)., Sommer C; 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.)., Gerlich DW; 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.)., Roth M; 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.)., Tontsch-Grunt U; 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.)., Wernitznig A; 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.)., Savarese F; 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.)., Hofmann MH; 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.)., Albrecht C; 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.)., Geiselmann L; 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.)., Reschke M; 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.)., Garin-Chesa P; 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.)., Zuber J; 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.)., Moll J; 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.)., Adolf GR; 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.)., Kraut N; 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.).
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2015 Mar; Vol. 352 (3), pp. 579-89. Date of Electronic Publication: 2015 Jan 09.
DOI:	10.1124/jpet.114.221150
Abstrakt:	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. (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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