Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor
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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; Peifer, Christian.
in: CHEMMEDCHEM, Jahrgang 13, Nr. 22, 20.11.2018, S. 2415-2426.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor
AU - Schmidt, Dorian
AU - Rodat, Theo
AU - Heintze, Linda
AU - Weber, Jantje
AU - Horbert, Rebecca
AU - Girreser, Ulrich
AU - Raeker, Tim
AU - Bußmann, Lara
AU - Kriegs, Malte
AU - Hartke, Bernd
AU - Peifer, Christian
N1 - © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2018/11/20
Y1 - 2018/11/20
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1002/cmdc.201800531
DO - 10.1002/cmdc.201800531
M3 - SCORING: Journal article
C2 - 30199151
VL - 13
SP - 2415
EP - 2426
JO - CHEMMEDCHEM
JF - CHEMMEDCHEM
SN - 1860-7179
IS - 22
ER -
