ArticleProceedings of the National Academy of Sciences of the United States of America2021
Mutation in Abl kinase with altered drug-binding kinetics indicates a novel mechanism of imatinib resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 67 citations in OpenAlex.
- Quantification of Binding of Small Molecules to Native Kinases by Flow Cytometry Reveals Divergence from Biochemical Affinities.Journal of the American Chemical Society · 2026Article
- More protein-ligand data are needed for AlphaFold-like models to enable drug discovery.Current opinion in structural biology · 2026Review
- Advances in BRET probes for intracellular target engagement studies.Nature chemical biology · 2026Review
- Altered residence time as a cause of drug resistance.Current opinion in structural biology · 2026Review
- Quantum medicine: A quantum-mechanical framework for redox biology, disease and precision medicine.Clinical and translational medicine · 2026Review
- The Discovery of Abl Kinase ATPase Activity and Its Implications in the Development of Straightforward Assays.ACS omega · 2025Article
- Rapid, accurate, and reproduciblemSphere · 2025Article
- More Sophisticated Is Not Always Better: A Comparison of Similarity Measures for Unsupervised Learning of Pathways in Biomolecular Simulations.The journal of physical chemistry. B · 2025Article
- Suppressing protein damage response to overcome multidrug resistance in cancer therapy.Cell discovery · 2025Article
- Multiple Molecule λ-Dynamics: Probing Drug Resistance with Concurrent Protein and Ligand Perturbations.The journal of physical chemistry letters · 2025Article
- Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding.The journal of physical chemistry. B · 2025Article
- Asciminib in the treatment of chronic myeloid leukemia in chronic phase.Future oncology (London, England) · 2025Review
- Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding.bioRxiv : the preprint server for biology · 2025Article
- Article
- Calculating Protein-Ligand Residence Times through State Predictive Information Bottleneck Based Enhanced Sampling.Journal of chemical theory and computation · 2024Article
- Quantitative Prediction of Dissociation Rates of PYK2 Ligands Using Umbrella Sampling and Milestoning.Journal of chemical theory and computation · 2024Article
- Calculating Protein-Ligand Residence Times Through State Predictive Information Bottleneck based Enhanced Sampling.bioRxiv : the preprint server for biology · 2024Article
- Review
- Data-driven classification of ligand unbinding pathways.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Potts Hamiltonian Models and Molecular Dynamics Free Energy Simulations for Predicting the Impact of Mutations on Protein Kinase Stability.The journal of physical chemistry. B · 2024Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Protein kinase inhibitors are potent anticancer therapeutics. For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for chronic myeloid leukemia by 80%, but 22 to 41% of patients acquire resistance to imatinib. About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain, where more than a hundred different mutations have been identified. Some mutations are located near the imatinib-binding site and cause resistance through altered interactions with the drug. However, many resistance mutations are located far from the drug-binding site, and it remains unclear how these mutations confer resistance. Additionally, earlier studies on small sets of patient-derived imatinib resistance mutations indicated that some of these mutant proteins were in fact sensitive to imatinib in cellular and biochemical studies. Here, we surveyed the resistance of 94 patient-derived Abl kinase domain mutations annotated as disease relevant or resistance causing using an engagement assay in live cells. We found that only two-thirds of mutations weaken imatinib affinity by more than twofold compared to Abl wild type. Surprisingly, one-third of mutations in the Abl kinase domain still remain sensitive to imatinib and bind with similar or higher affinity than wild type. Intriguingly, we identified three clinical Abl mutations that bind imatinib with wild type-like affinity but dissociate from imatinib considerably faster. Given the relevance of residence time for drug efficacy, mutations that alter binding kinetics could cause resistance in the nonequilibrium environment of the body where drug export and clearance play critical roles.
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