Source:http://linkedlifedata.com/resource/pubmed/id/17483355
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
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| pubmed:dateCreated |
2007-5-7
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| pubmed:abstractText |
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Angiogenesis Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/RON protein,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases
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| pubmed:status |
MEDLINE
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| pubmed:month |
May
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| pubmed:issn |
0008-5472
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| pubmed:author |
pubmed-author:AltonGordonG,
pubmed-author:ArangoMaria EME,
pubmed-author:BenderSteven LSL,
pubmed-author:ChristensenJames GJG,
pubmed-author:CuiJingrong JJJ,
pubmed-author:KoudriakovaTatiana BTB,
pubmed-author:KungPei-PeiPP,
pubmed-author:LeeJoseph HJH,
pubmed-author:LiQiuhuaQ,
pubmed-author:LosGerritG,
pubmed-author:McDonnellScott RSR,
pubmed-author:MroczkowskiBarbaraB,
pubmed-author:NambuMitchell DMD,
pubmed-author:YamazakiShinjiS,
pubmed-author:ZouHelen YHY
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| pubmed:issnType |
Print
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| pubmed:day |
1
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| pubmed:volume |
67
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
4408-17
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:17483355-Angiogenesis Inhibitors,
pubmed-meshheading:17483355-Animals,
pubmed-meshheading:17483355-Breast Neoplasms,
pubmed-meshheading:17483355-Cell Growth Processes,
pubmed-meshheading:17483355-Dogs,
pubmed-meshheading:17483355-Dose-Response Relationship, Drug,
pubmed-meshheading:17483355-Endothelial Cells,
pubmed-meshheading:17483355-Female,
pubmed-meshheading:17483355-Humans,
pubmed-meshheading:17483355-Male,
pubmed-meshheading:17483355-Mice,
pubmed-meshheading:17483355-Mice, Nude,
pubmed-meshheading:17483355-Neovascularization, Pathologic,
pubmed-meshheading:17483355-Phosphorylation,
pubmed-meshheading:17483355-Piperidines,
pubmed-meshheading:17483355-Protein Kinase Inhibitors,
pubmed-meshheading:17483355-Pyridines,
pubmed-meshheading:17483355-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:17483355-Signal Transduction,
pubmed-meshheading:17483355-Stomach Neoplasms,
pubmed-meshheading:17483355-Xenograft Model Antitumor Assays
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| pubmed:year |
2007
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| pubmed:articleTitle |
An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.
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| pubmed:affiliation |
Departments of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, California 92121, USA.
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| pubmed:publicationType |
Journal Article
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