Protein kinases are prime targets for anticancer therapies, but their close structural similarities can make achieving specificity for a particular kinase challenging, potentially leading to unwanted side effects. With this in mind, the authors aimed to redesign imatinib, focusing its specificity on C-Kit (also known as KIT) kinase inhibition (the therapeutic target for GIST) while reducing its effect on the kinase BCR–ABL (the therapeutic target for CML), which has also been linked to the cardiovascular side effects of the drug. Furthermore, they aimed to promote inhibition of JNK1, as previous research has indicated that this could ameliorate the adverse effects of imatinib on heart cells.
Their methodology is based on the knowledge that protein binding sites are typically regions where it is most energetically advantageous to exclude surrounding water from the backbone hydrogen bonds. Therefore, they first set out to identify specific kinase residues within the imatinib–kinase interface that possess a local propensity for water removal. They pinpointed the residue pair C673–G676 within the imatinib–C-Kit interface, whose dehydration propensity is absent in BCR–ABL owing to differences in the local environment. Using structural and molecular dynamics analysis, they predicted that addition of a methyl group to imatinib to form the reengineered compound, WBZ_4, would promote dehydration of the C673–G676 residue pair upon binding to C-Kit and stabilize the complex, while hampering any association of WBZ_4 with BCR–ABL. Notably, this modification additionally favoured the affinity of WBZ_4 for JNK1.
This is a preview of subscription content, access via your institution
