Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo
EM Kosciuczuk, D Saleiro, B Kroczynska… - Blood, The Journal …, 2016 - ashpublications.org
Blood, The Journal of the American Society of Hematology, 2016•ashpublications.org
Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in
the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic
translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation
of eIF4E may represent a unique approach for the treatment of AML. We provide evidence
for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with
suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E …
the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic
translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation
of eIF4E may represent a unique approach for the treatment of AML. We provide evidence
for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with
suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E …
Abstract
Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a unique approach for the treatment of AML. We provide evidence for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E phosphorylation in AML cells and suppresses primitive leukemic progenitors from AML patients in vitro and in an AML xenograft model in vivo. Our findings provide evidence for potent preclinical antileukemic properties of merestinib and support its clinical development for the treatment of patients with AML.
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