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

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.