Tutone Marco, Lauria Antonino, Almerico Anna Maria
Università di Palermo, Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari (STEMBIO) - Sezione di Chimica Farmaceutica e Biologica, Via Archirafi 32 - 90123 Palermo.
Bioinformation. 2011;7(6):296-8. doi: 10.6026/007/97320630007296. Epub 2011 Nov 20.
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.
据报道，c-kit原癌基因在造血细胞、小细胞肺癌和胃肠道间质瘤中存在过表达。c-kit在肿瘤中的表达具有临床重要性，这使得研究聚焦于这种酪氨酸激酶的抑制剂。伊马替尼（格列卫®）是首个用于治疗的化合物，但c-kit上的突变导致该治疗效果降低或无效。其他化合物可能对突变体有效，如舒尼替尼（索坦®），但仍迫切需要针对突变体的新型且最有效的抑制剂。我们报告了混合分子动力学/对接研究，旨在揭示伊马替尼、舒尼替尼及其他已知化合物对“守门人”突变体V654A和T670I产生抗性所涉及的分子机制。我们试图找出实际抑制剂的强弱特征，以便确定设计针对c-kit突变体的新型且最有效抑制剂的指导原则。
