ArticleProceedings of the National Academy of Sciences of the United States of America2018
Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
44 citing papers in PubMed, 64 citations in OpenAlex.
- The non-canonical CDK2 activator SPY1 uses separable mechanisms to activate phosphorylated and unphosphorylated CDK2.The Biochemical journal · 2026Article
- Cellular Context Influences Kinase Inhibitor Selectivity.Journal of medicinal chemistry · 2026Article
- The N-Myc MB0-MBI region interacts specifically and dynamically with the N-lobe of Aurora kinase A.Nature communications · 2026Article
- Cellular Selectivity Analyses Reveal Distinguishing Profiles for Type II Kinase Inhibitors.bioRxiv : the preprint server for biology · 2025Article
- Tyrosine-Mediated Static and Dynamic Quenching of a Receptor Tyrosine Kinase Biosensor Reveals Inhibitor Binding Modes and Kinase Conformations.ACS chemical biology · 2025Article
- Myc family proteins: Molecular drivers of tumorigenesis and resistance in neuroendocrine tumors.Biochimica et biophysica acta. Reviews on cancer · 2025Review
- Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders.Cell chemical biology · 2025Article
- Benchmarking Cross-Docking Strategies in Kinase Drug Discovery.Journal of chemical information and modeling · 2024Article
- Combinatorial strategies targeting NEAT1 and AURKA as new potential therapeutic options for multiple myeloma.Haematologica · 2024Article
- Latent allosteric control of protein interactions by ATP-competitive kinase inhibitors.Current opinion in structural biology · 2024Review
- Article
- Article
- Exploring the conformational landscapes of protein kinases: perspectives from FRET and DEER.Biochemical Society transactions · 2024Review
- Structural Dynamics of Protein Interactions Using Site-Directed Spin Labeling of Cysteines to Measure Distances and Rotational Dynamics with EPR Spectroscopy.Applied magnetic resonance · 2024Article
- Activating mutations drive human MEK1 kinase using a gear-shifting mechanism.The Biochemical journal · 2023Article
- Benchmarking Cross-Docking Strategies for Structure-Informed Machine Learning in Kinase Drug Discovery.bioRxiv : the preprint server for biology · 2023Article
- A biophysical framework for double-drugging kinases.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin.SLAS discovery : advancing life sciences R & D · 2023Article
- Structural basis for CEP192-mediated regulation of centrosomal AURKA.Science advances · 2023Article
- A biophysical framework for double-drugging kinases.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states. Profiling a panel of clinically relevant Aurora kinase inhibitors against the mitotic kinase Aurora A revealed a wide range of conformational preferences, with all inhibitors promoting either the active DFG-in state or the inactive DFG-out state, but to widely differing extents. Remarkably, these conformational preferences explain broad patterns of inhibitor selectivity across different activation states of Aurora A, with DFG-out inhibitors preferentially binding Aurora A activated by phosphorylation on the activation loop, which dynamically samples the DFG-out state, and DFG-in inhibitors binding preferentially to Aurora A constrained in the DFG-in state by its allosteric activator Tpx2. The results suggest that many inhibitors currently in clinical development may be capable of differentiating between Aurora A signaling pathways implicated in normal mitotic control and in melanoma, neuroblastoma, and prostate cancer. The technology is applicable to a wide range of clinically important kinases and could provide a wealth of valuable structure-activity information for the development of inhibitors that exploit differences in conformational dynamics to achieve enhanced selectivity.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.