Next Article in Journal
Early Life Stress Alters Expression of Glucocorticoid Stress Response Genes and Trophic Factor Transcripts in the Rodent Basal Ganglia
Next Article in Special Issue
A Novel Photoswitchable Azobenzene-Containing Local Anesthetic Ethercaine with Light-Controlled Biological Activity In Vivo
Previous Article in Journal
Sphingolipid Players in Multiple Sclerosis: Their Influence on the Initiation and Course of the Disease
Previous Article in Special Issue
Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate
Article

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

1
Stratingh Institute for Chemistry, University of Groningen, 9747 AG Groningen, The Netherlands
2
Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar 382355, India
3
Institute of Transformative BioMolecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8601, Japan
4
Department of Physics, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
5
Computational Structural Biology Unit, RIKEN-Center for Computational Science, Chuo, Kobe 650-0047, Japan
6
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; https://doi.org/10.3390/ijms23105326
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
Show Figures

Figure 1

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. https://doi.org/10.3390/ijms23105326

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. https://doi.org/10.3390/ijms23105326

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. https://doi.org/10.3390/ijms23105326

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop