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

Dorothea Rudolph, Maria Antonietta Impagnatiello, Claudia Blaukopf, Christoph Sommer, Daniel W Gerlich, Mareike Roth, Ulrike Tontsch-Grunt, Andreas Wernitznig, Fabio Savarese, Marco H Hofmann, Christoph Albrecht, Lena Geiselmann, Markus Reschke, Pilar Garin-Chesa, Johannes Zuber, Jürgen Moll, Günther R Adolf, Norbert Kraut

文献索引：J. Pharmacol. Exp. Ther. 352(3) , 579-89, (2015)

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摘要

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.