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Study of the role of “gatekeeper” mutations V654A and T670I of c-kit kinase in the interaction with inhibitors by means mixed molecular dynamics/docking approach
The over-expression of c-kit proto-oncogene has been reported in hematopoietic cells, small cell lung cancer, and gastrointestinal stromal tumors. The clinical importance of c-kit expression in tumors focused the research towards inhibitors of this tyrosine kinase. Imatinib (Gleevec®) was the first...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Biomedical Informatics
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280498/ https://www.ncbi.nlm.nih.gov/pubmed/22355224 |
Sumario: | The over-expression of c-kit proto-oncogene has been reported in hematopoietic cells, small cell lung cancer, and gastrointestinal stromal tumors. The clinical importance of c-kit expression in tumors focused the research towards inhibitors of this tyrosine kinase. Imatinib (Gleevec®) was the first compound used in therapy, but mutations on c-kit led to reduced effectiveness or ineffectiveness of this treatment. Other compounds are likely to be effective against mutants, such as Sunitinib (Sutent®), but the need for new and most effective inhibitors against mutants is still critical. We report mixed Molecular Dynamics/Docking study with the aim to unveil the molecular mechanism involved in the resistance of Imatinib, Sunitinib, and other known compounds against the “gatekeeper” mutants V654A e T670I. We tried to evidence strong and weak features of actual inhibitors in order to identify the guidelines to design new and most potent inhibitors against c-kit mutants. |
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