Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

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.

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

“…Unfortunately, the photoswitching of axitinib ( 1 ) is not reversible in aqueous solution due to a competing [2+2]-cycloaddition yielding a bioinactive dimer. Hence, we concluded that the original stilbene-like system of axitinib ( 1 ) is unsuitable as a reversible photoswitch, at least in aqueous solution [ 14 ].…”

“…However, this could not be observed for the final product 2 . Moreover, biological evaluation of the tautomer mixture of E -azoaxitinib ( E - 2a / E - 2b ) in a VEGFR-2 kinase assay revealed a decrease of the inhibitory activity (IC 50 = 415 nM, Figure S8 ) compared to E -axitinib (IC 50 = 19 nM) [ 14 ]. In fact, a simple azologization of axitinib is basically only partly useful, as azoaxitinib ( 2 ) is considered bioactive in the thermodynamically stable E -form.…”

Hemithioindigos for Cellular Photopharmacology: Desymmetrised Molecular Switch Scaffolds Enabling Design Control over the Isomer‐Dependency of Potent Antimitotic Bioactivity

“…The repertoire of molecular photoswitches is large, and many have been reported as photoswitch concepts (especially for cell‐free in vitro studies); for example, photoswitch concepts depending on fulgides, stilbenes, and diarylethenes have been reported for an interesting range of biological targets. However, azobenzenes remain essentially the only photoswitch to have been validated as a photopharmacological scaffold through multiple in cellulo to in vivo biological applications.…”

Reversible photoswitching of the DNA-binding properties of styrylquinolizinium derivatives through photochromic [2 + 2] cycloaddition and cycloreversion

“…Nevertheless, the photochromic nature of DNA-binding styryl dyes has not been applied to use them as photoswitchable DNA binders. Although, there is one reported example that demonstrates the deactivation of a stilbene tyrosine kinase inhibitor by a [2 + 2] photocycloaddition [59].…”