Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

Schmidt, Dorian, Rodat, Theo, Heintze, Linda, Weber, Jantje, Horbert, Rebecca, Girreser, Ulrich, Raeker, Tim, Bußmann, Lara, Kriegs, Malte, Hartke, Bernd and Peifer, Christian (2018) Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor ChemMedChem, 13 (22). pp. 2415-2426. DOI 10.1002/cmdc.201800531.

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Supplementary data:

Abstract

The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this context, the tyrosine kinase inhibitor axitinib, which contains a photosensitive stilbene-like moiety that allows for E/Z isomerization, is of interest. Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. The photoinduced E/Z isomerization of axitinib has been investigated to explore if its inhibitory effect can be turned "on" and "off", as triggered by light. Under controlled light conditions, (Z)-axitinib is 43 times less active than that of the E isomer in an VEGFR2 assay. Furthermore, it was proven that kinase activity in human umbilical vein cells (HUVECs) was decreased by (E)-axitinib, but only weakly affected by (Z)-axitinib. By irradiating (Z)-axitinib in vitro with UV light (λ=385 nm), it is possible to switch it almost quantitatively into the E isomer and to completely restore the biological activity of (E)-axitinib. However, switching the biological activity off from (E)- to (Z)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition, which yielded a biologically inactive axitinib dimer.

Document Type: Article
Keywords: angiogenesis; inhibitors; isomerization; kinases; photochemistry
Research affiliation: Kiel University > Kiel Marine Science
OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
DOI etc.: 10.1002/cmdc.201800531
ISSN: 18607179
Projects: Future Ocean
Date Deposited: 16 Jan 2019 11:13
Last Modified: 17 Jan 2019 09:03
URI: http://eprints.uni-kiel.de/id/eprint/45381

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