Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants.
Bottom Line: Interestingly, our in vitro study revealed that flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P).Our in vivo study consistently suggested that flumatinib had superior efficacy compared with imatinib or sunitinib against 32D cells with the secondary mutation Y823D.Molecular modeling of flumatinib docked to the KIT kinase domain suggested a special mechanism underlying the capability of flumatinib to overcome the drug-resistance conferred by activation loop mutations.
Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.Show MeSH
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Mentions: The crystal structure of KIT/imatinib complexes revealed that imatinib forms four hydrogen bonds with the residues Asp810, Glu640, Thr670 and Cys673 in the kinase domain, respectively.28 The main difference between imatinib and flumatinib is that a hydrogen atom in the former is substituted by a trifluoromethyl group in the latter (Fig. 5). To explore the molecular mechanism of imatinib resistance induced by secondary mutations in the KIT kinase domain, we analyzed the structure of the KIT/imatinib complex further. Considering that V654 is spatially proximate to imatinib and T670 forms a hydrogen bond with imatinib, we speculate that the secondary mutations in the drug/ATP binding site are likely to mediate imatinib resistance through steric factors and/or hydrogen bond disrupture (Fig. S4A); however, activation loop mutations do not seem to interact with imatinib directly, which suggests that these mutations may lead to imatinib resistance though different mechanisms. To understand the differential effects of flumatinib on the kinase activation of imatinib-resistant KIT double mutants, a molecular model was constructed from the coordinates of the crystal structure of the KIT/imatinib complex, and flumatinib was docked into the imatinib binding site. This docking model suggests that flumatinib locates in the same position and forms the same hydrogen bond interactions with the kinase domain as imatinib (Fig. S4B). Furthermore, the trifluoromethyl group of flumatinib seems to form additional interactions (van der Walls and/or hydrophobic interactions) with a hydrophobic pocket formed by side chains of residues Leu647, Ile653, Leu783, and Ile808 in the kinase domain (Fig. 5), and this indicates that flumatinib stands a good chance of having a higher affinity for the kinase domain. This hydrophobic pocket seems to be very important for the kinase activity, because substitution of any one of the four amino acids to an Ala destroys the transformation potential of KIT activating mutants (data not shown).
Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.