Abstract
Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC(50) values for autophosphorylation inhibition ranging between 0.15 and 1.5muM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCgamma and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain.
Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Adhesion / drug effects
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Cell Cycle / drug effects
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Indoles / pharmacology*
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Mice
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mutation / drug effects*
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Mutation / genetics
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NIH 3T3 Cells
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Oncogene Protein v-akt / metabolism
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Phospholipase C gamma / metabolism
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Phosphorylation / drug effects
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Piperazines / pharmacology*
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Protein Conformation
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Proto-Oncogene Proteins c-met / chemistry*
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Proto-Oncogene Proteins c-met / genetics*
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Proto-Oncogene Proteins c-met / metabolism
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STAT3 Transcription Factor / metabolism
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Sulfonamides / pharmacology*
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Wound Healing / drug effects
Substances
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((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
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Indoles
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Piperazines
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STAT3 Transcription Factor
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Sulfonamides
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Proto-Oncogene Proteins c-met
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Oncogene Protein v-akt
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Mitogen-Activated Protein Kinase 3
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Phospholipase C gamma