New Solid-Phase Kinase-Binding Matrix Facilitates Anti-Cancer Drug Search

Cancer researchers have employed a novel chemical proteomics technique to study the molecular action of two approved chronic myeloid leukemia (CML) drugs and one that is currently undergoing clinical testing.

Chemical proteomics is the use of chemical probes to study protein function and mechanism in a systems-based manner. Investigators at Cellzome, Inc. (Cambridge, UK and Heidelberg, DE) worked with their proprietary solid-phase kinase-binding matrix (Kinobeads) to measure the potency of potential drugs for more than 300 different kinases. Proteins bound to the matrix were quantified by mass spectrometry using isobaric tags for relative and absolute quantification.

The binding of drugs to their targets in cell lysates and in cells was assessed by measuring the competition with the affinity matrix. Analysis of signaling pathways downstream of target kinases was performed by mapping drug-induced changes in the phosphorylation state of the captured proteins.

Results were published in the August 26, 2007, online issue of the journal Nature Biotechnology. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel), and bosutinib (the experimental SKI-606) in K562 cells confirmed known targets including ABL and SRC family kinases and identified the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib.

Senior author Dr. Gerard Drewes, a vice-president at Cellzome, said, "With the Kinobeads technology, we can fully understand how kinase drugs work at the molecular level at the site of action inside cells and tissues. Not only can we measure the direct interaction of the drug with its native targets, but also how this affects signaling events in the cell.”


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