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Binding Kinetics Survey of the Drugged Kinome

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journal contribution
posted on 26.10.2018, 00:00 by Victoria Georgi, Felix Schiele, Benedict-Tilman Berger, Andreas Steffen, Paula A. Marin Zapata, Hans Briem, Stephan Menz, Cornelia Preusse, James D. Vasta, Matthew B. Robers, Michael Brands, Stefan Knapp, Amaury Fernández-Montalván
Target residence time is emerging as an important optimization parameter in drug discovery, yet target and off-target engagement dynamics have not been clearly linked to the clinical performance of drugs. Here we developed high-throughput binding kinetics assays to characterize the interactions of 270 protein kinase inhibitors with 40 clinically relevant targets. Analysis of the results revealed that on-rates are better correlated with affinity than off-rates and that the fraction of slowly dissociating drug–target complexes increases from early/preclinical to late stage and FDA-approved compounds, suggesting distinct contributions by each parameter to clinical success. Combining binding parameters with PK/ADME properties, we illustrate in silico and in cells how kinetic selectivity could be exploited as an optimization strategy. Furthermore, using bio- and chemoinformatics we uncovered structural features influencing rate constants. Our results underscore the value of binding kinetics information in rational drug design and provide a resource for future studies on this subject.