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Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274.
Journal article

Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274.

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  • 2009-09-29
Published in:
  • Cancer letters. - 2010
Animals
Blotting, Western
Cell Adhesion
Cell Cycle
Indoles
Mice
Mitogen-Activated Protein Kinase 3
Mutation
NIH 3T3 Cells
Oncogene Protein v-akt
Phospholipase C gamma
Phosphorylation
Piperazines
Protein Conformation
Proto-Oncogene Proteins c-met
STAT3 Transcription Factor
Sulfonamides
Wound Healing
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/hesso/documents/1234
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