Study of the role of “gatekeeper” mutations V654Aand T670I of c-kit kinase in the interaction withinhibitors by means mixed moleculardynamics/docking approach

The over-expression of c-kit proto-oncogene has been reported in hematopoietic cells, small cell lung cancer, and gastrointestinalstromal tumors. The clinical importance of c-kit expression in tumors focused the research towards inhibitors of this tyrosinekinase. Imatinib (Gleevec®) was the first compound used in therapy, but mutations on c-kit led to reduced effectiveness orineffectiveness of this treatment. Other compounds are likely to be effective against mutants, such as Sunitinib (Sutent®), but theneed for new and most effective inhibitors against mutants is still critical. We report mixed Molecular Dynamics/Docking studywith the aim to unveil the molecular mechanism involved in the resistance of Imatinib, Sunitinib, and other known compoundsagainst the “gatekeeper” mutants V654A and T670I. We tried to evidence strong and weak features of actual inhibitors in order toidentify the guidelines to design new and most potent inhibitors against c-kit mutants.