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J Am Chem Soc. 2018 Nov 21;140(46):15774-15782. doi: 10.1021/jacs.8b08048. Epub 2018 Nov 6.

Binding Kinetics Survey of the Drugged Kinome.

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Bayer AG, Drug Discovery, Pharmaceuticals , Müllerstraße 178 , 13353 Berlin , Germany.
Structural Genomics Consortium, Institute for Pharmaceutical Chemistry , Johann Wolfgang Goethe-University , Max-von-Laue-Straße 9 , 60438 Frankfurt am Main , Germany.
Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences , Johann Wolfgang Goethe-University , Max-von-Laue-Straße 15 , 60438 Frankfurt am Main , Germany.
Promega Corporation , 2800 Woods Hollow Road , Fitchburg , Wisconsin 53711 , United States.


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.


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