The interaction between a particular kinase and its chaperone proteins results in a change in the thermodynamic stability of the kinase. Using the HSP90 (heat shock protein 90) chaperone, Taipale et al. exploited this fact to create a thermodynamic sensor assay to profile the target specificity of 30 kinase inhibitors against >300 kinases in living cells. For example, they identified the ETV6–NTRK3 fusion oncogene as a new target of crizotinib. The assay could be extended to other chaperone–target interactions (HSP70–steroid hormone receptor and CDC37–kinase interactions), which suggests that the method could also be applicable to other small-molecule–target interactions.
References
Taipale, M. et al. Chaperones as thermodynamic sensors of drug–target interactions reveal kinase inhibitor specificities in living cells. Nature Biotech. 31, 630–637 (2013)
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Charlotte, H. Chaperones as thermodynamic sensors. Nat Rev Drug Discov 12, 580 (2013). https://doi.org/10.1038/nrd4094
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DOI: https://doi.org/10.1038/nrd4094
