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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2003-4-22
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pubmed:abstractText |
FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Endothelial Growth Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/FLT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Flt3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/Intercellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Lymphokines,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor A,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factors,
http://linkedlifedata.com/resource/pubmed/chemical/fms-Like Tyrosine Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/sunitinib
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0006-4971
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pubmed:author |
pubmed-author:AbramsTinya JTJ,
pubmed-author:CherringtonJulie MJM,
pubmed-author:HeinrichMichael CMC,
pubmed-author:HongWeiruW,
pubmed-author:LeeLeslie BLB,
pubmed-author:LouieSharianne GSG,
pubmed-author:ManningWilliam CWC,
pubmed-author:MurrayLesley JLJ,
pubmed-author:NgaiTheresa JTJ,
pubmed-author:O'FarrellAnne-MarieAM,
pubmed-author:SmolichBeverly DBD,
pubmed-author:TownAjiaA,
pubmed-author:WongLily MLM,
pubmed-author:YeeKevin W HKW,
pubmed-author:YuenHelene AHA
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
101
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3597-605
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12531805-Acute Disease,
pubmed-meshheading:12531805-Amino Acid Substitution,
pubmed-meshheading:12531805-Animals,
pubmed-meshheading:12531805-Antineoplastic Agents,
pubmed-meshheading:12531805-Apoptosis,
pubmed-meshheading:12531805-Bone Marrow Transplantation,
pubmed-meshheading:12531805-Endothelial Growth Factors,
pubmed-meshheading:12531805-Enzyme Inhibitors,
pubmed-meshheading:12531805-Female,
pubmed-meshheading:12531805-Humans,
pubmed-meshheading:12531805-Indoles,
pubmed-meshheading:12531805-Intercellular Signaling Peptides and Proteins,
pubmed-meshheading:12531805-Leukemia, Myeloid,
pubmed-meshheading:12531805-Lymphokines,
pubmed-meshheading:12531805-Mice,
pubmed-meshheading:12531805-Mice, Inbred NOD,
pubmed-meshheading:12531805-Mice, Nude,
pubmed-meshheading:12531805-Mice, SCID,
pubmed-meshheading:12531805-Neoplasm Proteins,
pubmed-meshheading:12531805-Phosphorylation,
pubmed-meshheading:12531805-Point Mutation,
pubmed-meshheading:12531805-Protein Processing, Post-Translational,
pubmed-meshheading:12531805-Protein Structure, Tertiary,
pubmed-meshheading:12531805-Proto-Oncogene Proteins,
pubmed-meshheading:12531805-Pyrroles,
pubmed-meshheading:12531805-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:12531805-Recombinant Fusion Proteins,
pubmed-meshheading:12531805-Signal Transduction,
pubmed-meshheading:12531805-Tandem Repeat Sequences,
pubmed-meshheading:12531805-Transfection,
pubmed-meshheading:12531805-Tumor Cells, Cultured,
pubmed-meshheading:12531805-Vascular Endothelial Growth Factor A,
pubmed-meshheading:12531805-Vascular Endothelial Growth Factors,
pubmed-meshheading:12531805-Xenograft Model Antitumor Assays,
pubmed-meshheading:12531805-fms-Like Tyrosine Kinase 3
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pubmed:year |
2003
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pubmed:articleTitle |
SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.
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pubmed:affiliation |
Preclinical Research and Exploratory Development, SUGEN, South San Francisco, CA 94080, USA. marie-ofarrell@sugen.com
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.
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