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The novel tyrosine ...
The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia
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- Eriksson, Anna (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin,Hematologi
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- Hermanson, Monica (author)
- Uppsala universitet,Medicinsk genetik
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- Wickström, Malin (author)
- Karolinska Institutet,Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Lindhagen, Elin (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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Ekholm, C (author)
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- Jenmalm Jensen, A (author)
- Karolinska Institutet
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Löthgren, A (author)
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Lehmann, F (author)
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- Larsson, Rolf (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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Parrow, V (author)
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- Höglund, Martin (author)
- Uppsala universitet,Hematologi
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(creator_code:org_t)
- 2012-08-03
- 2012
- English.
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In: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 2, s. e81-
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https://www.nature.c...
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https://urn.kb.se/re...
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Abstract
Subject headings
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- 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).
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Eriksson, Anna
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Hermanson, Monic ...
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Wickström, Malin
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Lindhagen, Elin
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Ekholm, C
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Jenmalm Jensen, ...
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show more...
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Löthgren, A
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Lehmann, F
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Larsson, Rolf
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Parrow, V
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Höglund, Martin
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
- Articles in the publication
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Blood Cancer Jou ...
- By the university
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Uppsala University
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Karolinska Institutet