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Mutation in Abl kinase with altered drug binding kinetics indicates a novel mechanism of imatinib resistance
/Agatha Lyczek, Benedict Tilman Berger, Aziz M Rangwala, YiTing Paung, Jessica Tom, Hannah Philipose, Jiaye Guo, Steven K Albanese, Matthew B Robers, Stefan Knapp, John D Chodera, Markus A Seeliger
Preprint ahead of publication: [bioRxiv]
Here, we characterize the biophysical mechanisms underlying mutants of Abl kinase associated with clinical drug resistance to targeted cancer therapies. We uncover a surprising novel mechanism of mutational resistance to kinase inhibitor therapy in which the off-rate for inhibitor unbinding is increased without affecting inhibitor affinity.