Richard Van Etten, Daniel Flynn and colleagues used the concept of 'switch control pocket'-targeted drugs. Such drugs would prevent a kinase from adopting its active conformation, even in the presence of mutations that promote the active conformation. The switch between inactive and active states is regulated by key amino acids in the switch pocket, and by studying the crystal structures of ABL1 bound to imatinib and dasatinib, and the structure of an active and related kinase LCK, Flynn and colleagues identified two amino acid residues, E282 and R386, which interact only in the inactive state. Two compounds that were designed to promote the interaction between these residues were able to inhibit ABL1 activity, and also had some efficacy against the T315I mutant. However, the authors reasoned that targeting an additional aspect of kinase activation — the ATP hinge region — could improve the binding energy and could more effectively hold active ABL1 mutants, such as T315I, in an inactive conformation. A third compound was designed that targeted the ATP hinge residue M318 and had similar efficacy to the first two compounds. By designing compounds that targeted both the switch pocket residues and the ATP hinge, the authors produced a drug, DCC-2036, that effectively stabilized both wild-type ABL1 and ABL1 T315I in an inactive conformation at low nanomolar concentrations.
Based on these and other preclinical data, DCC-2036 has entered Phase I clinical trials for patients with BRC–ABL1-positive leukaemia who have disease that is resistant to at least two approved tyrosine kinase inhibitors
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