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.
abstract: 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.
authors.affiliation: Università di Palermo, Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari (STEMBIO) - Sezione di Chimica Farmaceutica e Biologica, Via Archirafi 32 - 90123 Palermo.
authors.forename: Marco
authors.initials: M
authors.lastname: Tutone
authors.forename: Antonino
authors.initials: A
authors.lastname: Lauria
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Almerico