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Light-Control over Casein Kinase 1δ Activity with Photopharmacology: A Clear Case for Arylazopyrazole-Based Inhibitors

Stratingh Institute for Chemistry, University of Groningen, 9747 AG Groningen, The Netherlands
Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar 382355, India
Institute of Transformative BioMolecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8601, Japan
Department of Physics, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Computational Structural Biology Unit, RIKEN-Center for Computational Science, Chuo, Kobe 650-0047, Japan
Department of Radiology, Medical Imaging Center, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: DWI-Leibniz Institut für interaktive Materialien e.V., RWTH Aachen University, 52062 Aachen, Germany.
Academic Editors: Xavier Rovira Algans, Amadeu Llebaría and Xavier Gomez-Santacana
Int. J. Mol. Sci. 2022, 23(10), 5326;
Received: 12 April 2022 / Revised: 5 May 2022 / Accepted: 7 May 2022 / Published: 10 May 2022
(This article belongs to the Special Issue Advances in Photopharmacology)
Protein kinases are responsible for healthy cellular processes and signalling pathways, and their dysfunction is the basis of many pathologies. There are numerous small molecule inhibitors of protein kinases that systemically regulate dysfunctional signalling processes. However, attaining selectivity in kinase inhibition within the complex human kinome is still a challenge that inspires unconventional approaches. One of those approaches is photopharmacology, which uses light-controlled bioactive molecules to selectively activate drugs only at the intended space and time, thereby avoiding side effects outside of the irradiated area. Still, in the context of kinase inhibition, photopharmacology has thus far been rather unsuccessful in providing light-controlled drugs. Here, we present the discovery and optimisation of a photoswitchable inhibitor of casein kinase 1δ (CK1δ), important for the control of cell differentiation, circadian rhythm, DNA repair, apoptosis, and numerous other signalling processes. Varying the position at which the light-responsive azobenzene moiety has been introduced into a known CK1δ inhibitor, LH846, revealed the preferred regioisomer for efficient photo-modulation of inhibitory activity, but the photoswitchable inhibitor suffered from sub-optimal (photo)chemical properties. Replacement of the bis-phenyl azobenzene group with the arylazopyrazole moiety yielded a superior photoswitch with very high photostationary state distributions, increased solubility and a 10-fold difference in activity between irradiated and thermally adapted samples. The reasons behind those findings are explored with molecular docking and molecular dynamics simulations. Results described here show how the evaluation of privileged molecular architecture, followed by the optimisation of the photoswitchable unit, is a valuable strategy for the challenging design of the photoswitchable kinase inhibitors. View Full-Text
Keywords: photopharmacology; kinases; molecular photoswitches; arylazopyrazole photoswitches photopharmacology; kinases; molecular photoswitches; arylazopyrazole photoswitches
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MDPI and ACS Style

Schulte, A.M.; Kolarski, D.; Sundaram, V.; Srivastava, A.; Tama, F.; Feringa, B.L.; Szymanski, W. Light-Control over Casein Kinase 1δ Activity with Photopharmacology: A Clear Case for Arylazopyrazole-Based Inhibitors. Int. J. Mol. Sci. 2022, 23, 5326.

AMA Style

Schulte AM, Kolarski D, Sundaram V, Srivastava A, Tama F, Feringa BL, Szymanski W. Light-Control over Casein Kinase 1δ Activity with Photopharmacology: A Clear Case for Arylazopyrazole-Based Inhibitors. International Journal of Molecular Sciences. 2022; 23(10):5326.

Chicago/Turabian Style

Schulte, Albert M., Dušan Kolarski, Vidya Sundaram, Ashutosh Srivastava, Florence Tama, Ben L. Feringa, and Wiktor Szymanski. 2022. "Light-Control over Casein Kinase 1δ Activity with Photopharmacology: A Clear Case for Arylazopyrazole-Based Inhibitors" International Journal of Molecular Sciences 23, no. 10: 5326.

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