Modeling studies suggest that motesanib engages Kit via three polar interactions and a multitude of van der Waals contacts. In the context of this study, the most important of these interactions are those with thre onine 670 via a non classical CH O pseudo hydrogen bond and interactions with valine 654 through hydropho mutant destabilizes the selleck products inactivated form of Kit, in a way that the ability of the protein to adopt the DFG out conformation is much reduced or even elimi nated. thus, the mutation prevents both motesanib and imatinib from binding to the ATP pocket. The failure to potently inhibit the D816V mutation is a feature of Kit inhibitors in the clinic, with the exception for dasa tinib, which binds the DFG in, or activated form, of the kinase.

However, the ability of motesanib to inhibit the Y823 D mutant suggests Inhibitors,Modulators,Libraries that its activity may not be entirely restricted to an inactive protein con formation, or alternatively it may reflect that in contrast bic contacts. The fifteen fold loss of motesanib activity noted with the V560D V654A double mutant, compared with V560 D alone, is rationalized by the loss of two van der Waals contacts with alanine 654 in a similar fashion to that described for imatinib. Motesanib and imatinib have much diminished activity against the activation loop mutant. The D816V to the D816V mutation, the conformational equilibrium of the Y823 D mutant is not shifted permanently to the active conformation. The data from the present study are of translational rel evance, supporting evidence indicating that targeted therapy molecules with different binding sites and or mode of action may be required in the treatment of can cers for which mutations are the primary oncogenic event.

A recent study has demonstrated that differences in the conformational structure of Kit mutants influences the ability of sunitinib, and imatinib to bind and inhibit receptor autophosphorylation, thus providing a Inhibitors,Modulators,Libraries unique mechanism of drug resistance for each mutant that is unlikely to be overcome using a single treatment. Conclusions Inhibitors,Modulators,Libraries In summary, the results of this study demonstrate that different Kit mutations respond differently to motesanib or imatinib. This likely reflects Inhibitors,Modulators,Libraries differences Inhibitors,Modulators,Libraries in the mole cules mode of action. The data also show that motesanib is active against Kit mutations associated with resistance, suggesting that it may have clinical utility in the treat ment of patients with primary and secondary imatinib resistant GIST. Background Gastrointestinal stromal tumors are the most common mesenchymal neoplasms occurring throughout the entire region of the gastrointestinal tract and are considered to originate from intestitial cells selleck bio of Cajal, the pacemaker cells of the gut.