Light-control over casein kinase 1? activity with photopharmacology: a clear case for arylazopyrazole-based inhibitors

Show simple item record Schulte, Albert M. Kolarski, Dusan Sundaram, Vidya Srivastava, Ashutosh Tama, Florence Feringa, Ben L. Szymanski, Wiktor
dc.coverage.spatial Switzerland 2022-05-25T14:35:52Z 2022-05-25T14:35:52Z 2022-05
dc.identifier.citation Schulte, Albert M.; Kolarski, Dusan; Sundaram, Vidya; Srivastava, Ashutosh; Tama, Florence; Feringa, Ben L. and Szymanski, Wiktor, "Light-control over casein kinase 1? activity with photopharmacology: a clear case for arylazopyrazole-based inhibitors", International Journal of Molecular Sciences, DOI: 10.3390/ijms23105326, vol. 23, no. 10, May 2022. en_US
dc.identifier.issn 1661-6596
dc.identifier.issn 1422-0067
dc.description.abstract 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.
dc.description.statementofresponsibility by Albert M. Schulte, Dusan Kolarski, Vidya Sundaram, Ashutosh Srivastava, Florence Tama, Ben L. Feringa and Wiktor Szymanski
dc.format.extent vol. 23, no. 10
dc.language.iso en_US en_US
dc.publisher MDPI en_US
dc.subject Photopharmacology en_US
dc.subject Kinases en_US
dc.subject Molecular photoswitches en_US
dc.subject Arylazopyrazole photoswitches en_US
dc.title Light-control over casein kinase 1? activity with photopharmacology: a clear case for arylazopyrazole-based inhibitors en_US
dc.type Article en_US
dc.relation.journal International Journal of Molecular Sciences

Files in this item

Files Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record

Search Digital Repository


My Account