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Identification of A...
Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia
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- Eriksson, Anna (author)
- Uppsala universitet,Hematologi
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- Höglund, Martin (author)
- Uppsala universitet,Hematologi
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- Lindhagen, Elin (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Cancer Pharmacology and Informatics/Rolf Larsson
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- Åleskog, Anna (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Cancer Pharmacology and Informatics/Rolf Larsson
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- Hassan, Sadia Bashir (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Cancer Pharmacology and Informatics/Rolf Larsson
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Ekholm, Carina (author)
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Fhölenhag, Karin (author)
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Jensen, Annika Jenmalm (author)
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Löthgren, Agneta (author)
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Scobie, Martin (author)
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- Larsson, Rolf (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Cancer Pharmacology and Informatics/Rolf Larsson
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Parrow, Vendela (author)
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(creator_code:org_t)
- Elsevier BV, 2010
- 2010
- English.
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In: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 80:10, s. 1507-1516
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Aberrant signal transduction by mutant or overexpressed protein kinases has emerged as a promising target for treatment of acute myeloid leukemia (AML). We here present a novel low molecular weight kinase inhibitor, AKN-032, targeting the FMS-like tyrosine kinase 3 (FLT3) and discovered in a new type of screening funnel combining the target therapy approach with sequential cellular screens. AKN-032 was identified among 150 selected hits from three different high throughput kinase screens. Further characterization showed inhibitory activity on FLT3 enzyme with an IC50 of 70 nM. Western blot analysis revealed reduced autophosphorylation of the FLT3-receptor in AML cell line MV4-11 cells after exposure to AKN-032. Flow cytometry disclosed cytotoxic activity against MV4-11, but not against non-malignant 3T3-L1 fibroblast cells. Using a fluorometric microculture cytotoxicity assay, AKN-032 was tested against 15 cell lines and displayed a potent cytotoxic activity in AML cell lines MV4-11 (IC50 = 0.4 mu M) and Kasumi-1 (IC50 = 2.3 mu M). AKN-032 was also highly cytotoxic in tumor cells from AML patients in vitro. Furthermore, AKN-032 demonstrated significant antileukemic effect in a relatively resistant in vivo hollow fiber mouse model. No major toxicity was observed in the animals. In conclusion. AKN-032 is a promising new kinase inhibitor with significant in vivo and in vitro activity in AML Results from the hollow fiber mouse assay suggest a favorable toxicity profile. Future studies will focus on pharmacokinetic properties, toxicity as well as further clarifying the mechanisms of action of AKN-032 in AML.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- Acute myeloid leukemia
- New drug development
- Tyrosine kinase inhibitor
- FLT3
- MEDICINE
- MEDICIN
- PHARMACY
- FARMACI
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Eriksson, Anna
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Höglund, Martin
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Lindhagen, Elin
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Åleskog, Anna
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Hassan, Sadia Ba ...
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Ekholm, Carina
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show more...
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Fhölenhag, Karin
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Jensen, Annika J ...
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Löthgren, Agneta
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Scobie, Martin
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Larsson, Rolf
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Parrow, Vendela
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- About the subject
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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 Pharmaceutical S ...
- Articles in the publication
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Biochemical Phar ...
- By the university
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Uppsala University