Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells
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Lindquist_Chaperones as thermodynamic.pdf
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Author(s)
Taipale, Mikko
Krykbaeva, Irina
Whitesell, Luke
Santagata, Sandro
Zhang, Jianming
Liu, Qingsong
Gray, Nathanael S.
Lindquist, Susan
Date Issued
June 2013
Journal
Nature Biotechnology
Publisher
Nature Publishing Group
Citation
Taipale, Mikko, Irina Krykbaeva, Luke Whitesell, Sandro Santagata, Jianming Zhang, Qingsong Liu, Nathanael S Gray, and Susan Lindquist. “Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells.” Nature Biotechnology 31, no. 7 (June 30, 2013): 630-637.
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1038/nbt.2620
