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Kinases are enzymes that regulate cell signaling by adding phosphate groups in cell signaling, and their dysregulation is linked to cancer progression. Targeting kinases with small-molecule inhibitors is a promising therapeutic strategy but developing selective inhibitors to prevent unintended off-target effects remains challenging due to structural similarities among kinases. In a recent , published in Molecular & Cellular Proteomics, Wouter van Bergen of the University of Utrecht, The Netherlands, introduces a novel technique that improves kinase target identification, to help to enhance drug specificity and reduce unintended interactions.

Unlike traditional methods, this study used phosphonate affinity tags, which are chemical probes that mimic phosphate groups, for monitoring site-specific drug binding. These tags facilitate the distinction between closely related kinases, helping to reveal off-target effects. Using a combination of cell biology, biochemical reactions and proteomics, the group demonstrated that phosphonate affinity tags are a useful tool for high-specificity kinase inhibitor profiling. In human lung carcinoma cells treated with a tyrosine kinase inhibitor, they used covalent linkage formation between a broad-spectrum kinase targeting activity-based probe and the phosphonate tag, followed by proteomic analysis, to identify effective competition between the inhibitor, a key indicator of target engagement. This approach also uncovered previously unknown off-target interactions, confirming its sensitivity and accuracy.

By refining kinase inhibitor profiling, this technique opens the door to more precise cancer therapies. It could support personalized medicine approaches by tailoring treatments to individual patients, improving both safety and efficacy.