Taming the induced folding of drug-targeted kinases

Kinases have been exploited as anticancer drug targets but their conformational plasticity hinders the progress of structure-based design because the target might structurally adapt in unpredictable ways upon ligand binding. Thus, rational design of kinase inhibitors typically avoids targeting floppy regions. However, the level of amino acid conservation in such regions across homologous kinases is relatively low compared with structured regions, making them desirable binding sites to control specificity. Thus, we advocate for a much needed design concept to target unstructured regions. This concept applies to cases in which the floppy region cannot sustain structure owing to deficient packing. Thus, we propose the design of drugs that improve the packing quality of the kinase structure upon association, thereby steering induced folding. This concept is validated by dynamically examining structural adaptations promoted by imatinib redesigns intended to control drug specificity.