Death by a thousand cuts through kinase inhibitor combinations that maximize selectivity and enable rational multitargeting

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Outhwaite IR, Singh S, Berger B-T, Knapp S, Chodera JD, Seeliger MA
eLife 12:e86189, 2024 [DOI] [bioRxiv] [GitHub]

We show how combinations of kinase inhibitors can achieve selectivity gains for rational kinase polypharmacology.

Mutation in Abl kinase with altered drug binding kinetics indicates a novel mechanism of imatinib resistance

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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.