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2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach

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Abstract

In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologically less potent. Herein we report the design, synthesis and photochemical/inhibitory characterization of new photoswitchable kinase inhibitors targeting p38a MAPK and CK15. A well characterized inhibitor scaffold was used to attach arylazo- and diazocine moieties. When the isolated isomers, or the photostationary state (PSS) of isomers, were tested in commonly used in vitro kinase assays, however, only small differences in activity were observed. X-ray analyses of ligand-bound p38α MAPK and CK15 complexes revealed dynamic conformational adaptations of the protein with respect to both isomers. More importantly, irreversible reduction of the azo group to the corresponding hydrazine was observed. Independent experiments revealed that reducing agents such as DTT (dithiothreitol) and GSH (glutathione) that are typically used for protein stabilization in biological assays were responsible. Two further sources of error are the concentration dependence of the E-Z-switching efficiency and artefacts due to incomplete exclusion of light during testing. Our findings may also apply to a number of previously investigated azobenzene-based photoswitchable inhibitors.

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Acknowledgements

The authors from Kiel university acknowledge financial support by the Deutsche Forschungsgesellschaft (DFG) within the Sonderforschungsbereich 677, “Function by Switching”. Chiara Ianes is financially supported by a grant of the medical faculty of Ulm University (“Bausteinprogramm”)awarded to Joachim Bischof. Work in the lab of Uwe Knippschild was supported by the DFG (KN356/6-1, and SFB 1149, project B04). Daniel Rauh is thankful for support from the German Federal Ministry for Education and Research (NGFNPlus and e:Med) (Grant No. BMBF 01GS08104, 01ZX1303C), the Deutsche Forschungsgemeinschaft (DFG) and the German federal state North Rhine Westphalia (NRW) and the European Union (European Regional Development Fund: Investing In Your Future) (EFRE-800400). The crystallographic experiments leading to these results have received funding from the European Community'sSeventh Framework Programme (FP7/2007-2013) under grant agreement No. 283570 (BioStruct-X). CKLS crystals were growninthe Cologne Crystallization facility (http://C2f.uni-koeIn.de/). We thank the staff at the Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland for their support during data collection. We gratefully acknowledge the help of Dr Dieter Schollmeyer, University of Mainz, Institute for Organic Chemistry, Germany, for X-ray analysis of compound 13.

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Authors and Affiliations

  1. Otto Diets-Institute of Organic Chemistry, Christian Albrechts University Kiel, Otto-Hahn-Piatz 4, 24118, Kiel, Germany

    Miriam Schehr, Julia Ewert, Marc Lehr & Rainer Herges

  2. Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081, Ulm, Germany

    Chiara Lanes

  3. Faculty of Chemistry and Chemical Biology, TU Dortmund University and Drug Discovery Hub Dortmund (DDHD) am Zentrum für integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Straße 4a, 44227, Dortmund, Germany

    Jörn Weisner, Matthias P. Müller & Daniel Rauh

  4. Institute of Pharmacy, Christian Albrechts University Kiel, Gutenbergstraße 76, 24118, Kiel, Germany

    Linda Heintze, Uwe Knippschild & Christian Peifer

  5. Department of Chemistry, University of Cologne, Otto-Fischer-Straße 12-14, 50674, Cologne, Germany

    Christian Pichlo, Julia Charl, Elena Brunstein & Ulrich Baumann

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  1. Miriam Schehr
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Correspondence to Christian Peifer or Rainer Herges.

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Schehr, M., Lanes, C., Weisner, J. et al. 2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach. Photochem Photobiol Sci 18, 1398–1407 (2019). https://doi.org/10.1039/c9pp00010k

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