Reference Detail

Ref Type Journal Article
PMID (23811600)
Authors Taipale M, Krykbaeva I, Whitesell L, Santagata S, Zhang J, Liu Q, Gray NS, Lindquist S
Title Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells.
Journal Nature biotechnology
Vol 31
Issue 7
Date 2013 Jul
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
P465S missense gain of function ABL1 P465S lies within the protein kinase domain of the Abl1 protein (UniProt.org). P465S has been demonstrated to confer resistance to allosteric Abl1 inhibitors (PMID: 25849130, PMID: 27890928) and results in increased kinase activity and transformation in cultured cells (PMID: 27890928). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6-NTRK3 acute myeloid leukemia sensitive Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xalkori (crizotinib) inhibited ETV6-NTRK3 activity, reduced cell growth in a human acute myeloid leukemia cell line harboring ETV6-NTRK3, and had anti-tumor activity in xenograft models (PMID: 23811600). 23811600