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Ref Type Journal Article
PMID (22864397)
Authors Eriksson A, Hermanson M, Wickström M, Lindhagen E, Ekholm C, Jenmalm Jensen A, Löthgren A, Lehmann F, Larsson R, Parrow V, Höglund M
Title The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia.
Journal Blood cancer journal
Vol 2
Issue
Date 2012 Aug 03
URL
Abstract Text 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 (IC(50)=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 IC(50) 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).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AKN-028 AKN-028 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AKN-028 BVT-II|AKN028 FLT3 Inhibitor 55 KIT Inhibitor 51 AKN-028 inhibits wild-type and mutant forms of FLT3 and KIT, potentially resulting in decreased tumor cell proliferation (PMID: 22864397).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown acute myeloid leukemia not applicable AKN-028 + Daunorubicin Preclinical - Cell culture Actionable In a preclinical study, the sequential treatment of Cerubidine (daunorubicin) and AKN-028 resulted in a syntergistic effect in acute myeloid leukemia cells in culture, demonstrating antileukemic activity (PMID: 22864397). 22864397
Unknown unknown acute myeloid leukemia not applicable AKN-028 + Cytarabine Preclinical - Cell culture Actionable In a preclinical study, the sequential treatment of Cytosar-U (cytarabine) and AKN-028 resulted in a syntergistic effect in acute myeloid leukemia cells in culture, demonstrating antileukemic activity (PMID: 22864397). 22864397
Unknown unknown acute myeloid leukemia not applicable AKN-028 Preclinical - Cell culture Actionable In a preclinical study, AKN-028 treatment induced apoptosis in acute myeloid leukemia cells in culture and inhibited growth and resulted in decreased tumor mass in acute myeloid leukemia cell line xenograft models (PMID: 22864397). 22864397