ArticleNature biotechnology2013
Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells.
Article in Nature biotechnology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 137 citations in OpenAlex.
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- CDK3 induces neuronal death and brain atrophy in Alzheimer's disease.Nature aging · 2026Article
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- Advances in the structures, mechanisms and targeting of molecular chaperones.Signal transduction and targeted therapy · 2025Review
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- Factors affecting protein recovery during Hsp40 affinity profiling.Analytical and bioanalytical chemistry · 2024Article
- A fluorescence-based sensor for calibrated measurement of protein kinase stability in live cells.Protein science : a publication of the Protein Society · 2024Article
- Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis.Nature communications · 2024Article
- Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers.Cell reports · 2024Article
- A Fluorescence-Based Sensor for Calibrated Measurement of Protein Kinase Stability in Live Cells.bioRxiv : the preprint server for biology · 2023Article
- Pervasive mislocalization of pathogenic coding variants underlying human disorders.bioRxiv : the preprint server for biology · 2023Article
- The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations.Cancers · 2023Article
- MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia.Leukemia · 2023Article
- Molecular determinants of Hsp90 dependence of Src kinase revealed by deep mutational scanning.Protein science : a publication of the Protein Society · 2023Article
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- Molecular matched targeted therapies for primary brain tumors-a single center retrospective analysis.Journal of neuro-oncology · 2022Article
- Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities.MedComm · 2022Review
- Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells.Scientific reports · 2022Article
17 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The interaction between the HSP90 chaperone and its client kinases is sensitive to the conformational status of the kinase, and stabilization of the kinase fold by small molecules strongly decreases chaperone interaction. Here we exploit this observation and assay small-molecule binding to kinases in living cells, using chaperones as 'thermodynamic sensors'. The method allows determination of target specificities of both ATP-competitive and allosteric inhibitors in the kinases' native cellular context in high throughput. We profile target specificities of 30 diverse kinase inhibitors against >300 kinases. Demonstrating the value of the assay, we identify ETV6-NTRK3 as a target of the FDA-approved drug crizotinib (Xalkori). Crizotinib inhibits proliferation of ETV6-NTRK3-dependent tumor cells with nanomolar potency and induces the regression of established tumor xenografts in mice. Finally, we show that our approach is applicable to other chaperone and target classes by assaying HSP70/steroid hormone receptor and CDC37/kinase interactions, suggesting that chaperone interactions will have broad application in detecting drug-target interactions in vivo.
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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.