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.