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Assays & screens

Assay for profiling kinase inhibitor-target interaction in cells

In vitro and cell culture studies suggest an assay for monitoring kinase inhibitor-sensitive chaperone-kinase interactions could help identify targets of kinase inhibitors in cells. In vitro, luciferase-tagged heat shock protein 90 (Hsp90) directly bound to BCR-ABL tyrosine kinase, producing a luminescent signal in the assay. In this assay, the nonselective BCR-ABL inhibitor Gleevec imatinib decreased both Hsp90 binding to BCR-ABL and luminescent signal compared with no treatment. The assay showed that a panel of inhibitors selectively blocked kinase-chaperone interactions in a manner consistent with known specificities and identified neurotrophic tyrosine kinase receptor 3 (NTRK3; TrkC) as an additional target of Xalkori crizotinib. Next steps include testing Xalkori in models for tumors caused by NTRK3 mutations, including fibrosarcomas.
Novartis AG markets Gleevec to treat chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors.
Pfizer Inc. markets Xalkori, a dual inhibitor of c-Met receptor tyrosine kinase and anaplastic lymphoma kinase (ALK), to treat non-small cell lung cancer (NSCLC).

SciBX 6(30); doi:10.1038/scibx.2013.803
Published online Aug. 8, 2013

Patent pending; available for licensing

Taipale, M. et al. Nat. Biotechnol.; published online June 30, 2013;
Contact: Susan Lindquist, Whitehead Institute for Biomedical Research, Cambridge, Mass.