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Angew Chem Int Ed Engl. 2018 Apr 9;57(16):4372-4385. doi: 10.1002/anie.201707875. Epub 2018 Feb 2.

The Cysteinome of Protein Kinases as a Target in Drug Development.

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Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
Institute for Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Strasse 9, 60438, Frankfurt am Main, Germany.
Department of Pharmaceutical/Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
German Cancer Consortium DKTK, Standort Tübingen, Germany.
German Cancer Consortium DKTK, Standort Frankfurt/Mainz, Germany.
Structural Genomics Consortium and Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 15, 60438, Frankfurt am Main, Germany.


Drugs that function through covalent bond formation represent a considerable fraction of our repository of effective medicines but safety concerns and the complexity of developing covalent inhibitors has rendered covalent targeting a less attractive strategy for rational drug design. The recent approval of four covalent kinase inhibitors and the development of highly potent covalent kinase probes with exceptional selectivity has raised significant interest in industry and academic research and validated the concept of covalent kinase targeting for clinical applications. The abundance of cysteines at diverse positions in and around the kinase active site suggests that a large fraction of kinases can be targeted by covalent inhibitors. Herein, we review recent developments of this rapidly growing area in kinase drug development and highlight the unique opportunities and challenges of this strategy.


covalent inhibitors; cysteine; cysteinome; kinases; selectivity


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