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.

Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations

Kevin Hauser, Christopher Negron, Steven K. Albanese, Soumya Ray, Thomas Steinbrecher, Robert Abel, John D. Chodera, and Lingle Wang.
Communications Biology 1:70, 2018 [DOI] [PDF] [input files and analysis scripts]

In our first collaborative paper with Schrödinger, we present the first comprehensive benchmark assessing the ability for alchemical free energy calculations to predict clinical mutational resistance or susceptibility to targeted kinase inhibitors using the well-studied kinase Abl, the target of therapy for chronic myelogenous leukemia (CML).