Axitinib is an approved drug targeting tyrosine kinases including the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. Interestingly, axitinib contains a stilbene-like double bond allowing for E/Z isomerization. In this study, we investigated the photoinduced E/Z isomerization of axitinib to explore if its inhibitory effect can be turned "on" and "off", triggered by light. Compared to the E-isomer, the absorption of the Z-isomer is red-shifted indicating reversible photoswitching properties. When both isolated isomers were measured in a commercial available profiling under ambient light, no differences of biological activities could be determined. However, under controlled light conditions we could demonstrate that (Z) axitinib is 43 times less active compared to the (E) isomer in an VEGFR2 assays. Furthermore, we proved that kinase activity in HUVEC assays is reduced by (E)-axitinib, but only weakly affected by (Z) axitinib. By irradiating (Z) axitinib in vitro with UV light (385 nm) it is possible to switch it almost quantitatively to the (E)-isomer and to completely restore the biological activity of (E) axitinib. However, vice versa switching the biological activity "off" from (Z)- to (E)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition yielding a biologically inactive axitinib-dimer.
ChemMedChem. 2018 Sep 10 [Epub ahead of print]
Christian Peifer, Dorian Schmidt, Theo Rodat, Linda Heintze, Jantje Weber, Rebecca Horbert, Ulrich Girreser, Tim Raeker, Lara Bußmann, Malte Kriegs, Bernd Hartke
Christian Albrechts University, Department of Pharmaceutical Chemistry, Gutenbergstrasse 76, 24118, Kiel, GERMANY., Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, GERMANY., Christian-Albrechts-University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, GERMANY., Christian-Albrechts-University of Kiel, Institute for Physical Chemistry, Max-Eyth-Strasse 1, 24118, Kiel, GERMANY., University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Department of Otorhinolaryngology and Head and Neck Surgery, Martinistr. 52, 20246, Hamburg, GERMANY., University Medical Center Hamburg-Eppendorf, Laboratory of Radiobiology & Experimental Radiooncology and UCCH Kinomics Core Facility, Martinistr. 52, 20246, Hamburg, GERMANY., Christian-Albrechts-University of Kiel, Institute of Physical Chemistry, Max-Eyth-Strasse 1, 24118, Kiel, GERMANY.