Originating in the lab of Oncode Investigator Mario van der Stelt (Leiden University) and further on with support from collaborators such as Oncode Accelerator and Roche, the discovery has led to the development of CellEKT, a chemical proteomics platform designed to assess the selectivity of kinase inhibitors. This advancement holds promise for improving the development of targeted cancer therapies.
Protein kinases are critical regulators of cellular processes, and their dysregulation is often implicated in cancer. With over 500 kinases encoded in the human genome, developing inhibitors that selectively target specific kinases without affecting others remains a significant challenge in oncology drug development.
Addressing this issue, Oncode Researcher Joel Ruegger and the team in the lab of Oncode Investigator Mario van der Stelt have introduced CellEKT (Cellular Endogenous Kinase Targeting) - a chemical proteomics platform that enables the comprehensive profiling of kinase inhibitor selectivity within living cells. By utilizing novel sulfonyl fluoride-based probes—ALX005 and ALX011—alongside the established XO44 probe, CellEKT can assess the binding interactions of drug candidates across a broad spectrum of kinases.
The platform operates by introducing these probes into cellular environments, where they compete with kinase inhibitors for binding sites. Subsequent mass spectrometry analysis allows for the quantification of inhibitor engagement with various kinases, providing insights into the selectivity and potential off-target effects of the compounds under investigation.
In collaboration with partners, including Roche and Oncode Accelerator, the CellEKT platform has been validated using a range of kinase inhibitors. This validation demonstrated CellEKT's capability to generate detailed interaction profiles, facilitating the identification of compounds with optimal selectivity profiles for further development.
Oncode Researcher Joel Ruegger, a key contributor to the development of CellEKT, emphasized the platform's potential impact: "By enabling a more precise assessment of kinase inhibitor selectivity early in the drug development process, CellEKT can help streamline the identification of promising therapeutic candidates and reduce the likelihood of adverse side effects."
The introduction of CellEKT represents a significant step forward in the pursuit of more effective and safer targeted cancer therapies. By providing a robust tool for early-stage evaluation of drug selectivity, this platform supports the development of treatments with improved efficacy and reduced toxicity.
You can read the research manuscript on CellEKT in Molecular & Cellular Proteomics.
