Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo.
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.
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
Ewa M
EM
Kosciuczuk
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and.
Diana
D
Saleiro
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and.
Barbara
B
Kroczynska
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
Elspeth M
EM
Beauchamp
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and.
Frank
F
Eckerdt
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and.
Gavin T
GT
Blyth
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and.
Sameem M
SM
Abedin
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and.
Francis J
FJ
Giles
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and.
Jessica K
JK
Altman
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
Leonidas C
LC
Platanias
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D000073840:Copper-Transporting ATPases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D027682:Cation Transport Proteins; D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D009363:Neoplasm Proteins; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases