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Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells.

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.

journal_name

Nat Biotechnol

journal_title

Nature biotechnology

authors

Taipale M,Krykbaeva I,Whitesell L,Santagata S,Zhang J,Liu Q,Gray NS,Lindquist S

doi

10.1038/nbt.2620

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

630-7

issue

7

eissn

1087-0156

issn

1546-1696

pii

nbt.2620

journal_volume

31

pub_type

杂志文章

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