Abstract
Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nℳ), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μℳ). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).
Highlights
Despite recent progress in understanding the pathogenesis and molecular genetics of acute myeloid leukemia (AML), the prognosis for most patients is still dismal
We have previously shown that 2-aminopyrazine tyrosine kinase inhibitors (TKIs) can induce significant in vitro activity in AML, seemingly irrespective of FMS-like receptor tyrosine kinase 3 (FLT3) mutation status.[20]
AKN-028 induced a dose-dependent inhibition of the FLT3 kinase with an IC50 value of 6 nM (n 1⁄4 20), as determined by a kinase inhibition assay; sunitinib was tested for comparison (Figure 1c)
Summary
Despite recent progress in understanding the pathogenesis and molecular genetics of acute myeloid leukemia (AML), the prognosis for most patients is still dismal. Genetic changes involving protein tyrosine kinases leading to deregulation of intracellular signaling pathways, have been linked to leukemogenesis as well as to progression of the leukemic disease.[3] Activation of the FMS-like receptor tyrosine kinase 3 (FLT3), expressed on early multipotent hematopoietic cells, promotes cell survival and proliferation by interacting with multiple downstream targets including the AKT, STAT and MAP-kinase pathways.[4,5] In the majority of patients with AML, FLT3 is overexpressed.[6,7] Activating FLT3 mutations occur in up to 30% of patients, out of which three-fourth consists of FLT3-internal tandem duplications (FLT3-ITD) located in the juxtamembrane domain, and approximately one-fourth of point mutations in the FLT3-tyrosine kinase domain (FLT3-TKD),[8] the former being associated with increased risk of relapse and poor overall survival.[9,10,11] a high frequency of mutations in the tyrosine kinase KIT has been reported in core binding factor AML, with an adverse impact on prognosis.[12,13]
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