Oss, January, 2nd, 2017 – NTRC has made available the kinetic data of 80 kinase inhibitors on their targets in a research article in the Journal of Molecular Biology. This is the largest data base of association and dissociation rate constants of kinase inhibitors available to date. In total, 46 protein tyrosine, serine/threonine and lipid kinases were studied, including well-known drug targets such as the epidermal growth factor receptor (EGFR) and the δ-isoform of phosphoinositide 3-kinase (PI3Kδ). Kinetic constants were determined on NTRC’s ResidenceTimer™ platform using recombinant kinases from Carna Biosciences, Inc. (Kobe, Japan).
Kinases are the target of more than thirty registered small molecule drugs, while more than 300 kinase inhibitors are currently investigated in clinical studies. With the growing interest in the targeting of kinases in non-cancer indications and chronic diseases, there is an increased demand for selective inhibitors. The relative selectivity of kinase inhibitors is commonly determined by measuring their inhibitory potency (IC50) in a large panel of enzyme assays. These assays are usually performed at different ATP concentrations and with different substrates, in a closed system with a fixed concentration of inhibitor. In living systems the concentration of inhibitors is continuously changing. The time a compound resides on its target, or ‘target residence time’ (τ), is therefore a better predictor of its biological activity than its IC50 in enzyme assays. Thus, compared to traditional enzyme assays, ResidenceTimer™ measurements allow the determination of the binding kinetics and selectivity of kinase inhibitors in a system that better resembles real life biology than assays in equilibrium or end-point assays.
In the article in Journal of Molecular Biology a number of comparative studies are presented for, a.o., different Aurora and PI3K inhibitors. These case studies provide clear arguments to include target residence time measurements in kinase inhibitor drug discovery programs. To access the article follow: http://dx.doi.org/10.1016/j.jmb.2016.12.019
NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact [email protected]