TY - JOUR T1 - Efficacy and Mechanism of Action of Volasertib, a Potent and Selective Inhibitor of Polo-Like Kinases, in Preclinical Models of Acute Myeloid Leukemia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 579 LP - 589 DO - 10.1124/jpet.114.221150 VL - 352 IS - 3 AU - Dorothea Rudolph AU - Maria Antonietta Impagnatiello AU - Claudia Blaukopf AU - Christoph Sommer AU - Daniel W. Gerlich AU - Mareike Roth AU - Ulrike Tontsch-Grunt AU - Andreas Wernitznig AU - Fabio Savarese AU - Marco H. Hofmann AU - Christoph Albrecht AU - Lena Geiselmann AU - Markus Reschke AU - Pilar Garin-Chesa AU - Johannes Zuber AU - Jürgen Moll AU - Günther R. Adolf AU - Norbert Kraut Y1 - 2015/03/01 UR - http://jpet.aspetjournals.org/content/352/3/579.abstract N2 - 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. ER -