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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...

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Detalles Bibliográficos
Autores principales: Tutone, Marco, Lauria, Antonino, Almerico, Anna Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Biomedical Informatics 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280498/
https://www.ncbi.nlm.nih.gov/pubmed/22355224
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author Tutone, Marco
Lauria, Antonino
Almerico, Anna Maria
author_facet Tutone, Marco
Lauria, Antonino
Almerico, Anna Maria
author_sort Tutone, Marco
collection PubMed
description 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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spelling pubmed-32804982012-02-21 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 Tutone, Marco Lauria, Antonino Almerico, Anna Maria Bioinformation Hypothesis 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. Biomedical Informatics 2011-11-20 /pmc/articles/PMC3280498/ /pubmed/22355224 Text en © 2011 Biomedical Informatics This is an open-access article, which permits unrestricted use, distribution, and reproduction in any medium, for non-commercial purposes, provided the original author and source are credited.
spellingShingle Hypothesis
Tutone, Marco
Lauria, Antonino
Almerico, Anna Maria
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Hypothesis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280498/
https://www.ncbi.nlm.nih.gov/pubmed/22355224
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