title: Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells.
abstract: Kit is a membrane-bound tyrosine kinase and receptor for stem cell factor (SCF) with a crucial role in hematopoiesis. Mutations of KIT occur in almost half of patients with core-binding factor leukemias, in which they have been associated with worse outcome. Development of new compounds targeting Kit may therefore hold promise for therapy. We investigated the activity and mechanism of action of APcK110, a novel Kit inhibitor, in the mastocytosis cell line HMC1.2 (KITV560G and KITD816V), acute myeloid leukemia (AML) lines OCIM2 and OCI/AML3 (both wild-type), and primary samples from patients with AML. We show that (a) APcK110 inhibits proliferation of the mastocytosis cell line HMC1.2 and the SCF-responsive cell line OCI/AML3 in a dose-dependent manner; (b) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than the clinically used Kit inhibitors imatinib and dasatinib and at least as potent as cytarabine; (c) APcK110 inhibits the phosphorylation of Kit, Stat3, Stat5, and Akt in a dose-dependent fashion, showing activity of APcK110 on Kit and its downstream signaling pathways; (d) APcK110 induces apoptosis by cleavage of caspase-3 and poly(ADP-ribose) polymerase; and (e) APcK110 inhibits proliferation of primary AML blasts in a clonogenic assay but does not affect proliferation of normal colony-forming cells. Although APcK110 activity may partly depend on cytokine responsiveness (e.g., SCF) and not exclusively KIT mutation status, it remains a potent inhibitor of AML and mastocytosis cell lines and primary AML samples. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML.
authors.affiliation: Department of Leukemia , The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. sfaderl@mdanderson.org
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Pal
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: David
authors.initials: D
authors.lastname: Maxwell
authors.forename: Quin
authors.initials: Q
authors.lastname: Van
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Liu
authors.forename: Inbal
authors.initials: I
authors.lastname: Hazan-Halevy
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000068877:Imatinib Mesylate; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C541943:(4-(7-(3,5-dimethyloxyphenyl)-1H-pyrazolo(3,4)pyridin-6-yl)-4-fluoro)benzene; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019089:Stem Cell Factor; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D051058:Oncogene Protein v-akt; D020169:Caspases; D000069439:Dasatinib