Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

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. Back and forth: Axitinib is an approved drug licensed for second‐line therapy of renal cell carcinoma that shows reasonable photoswitching properties by chance. The photoinduced E/Z isomerization of axitinib is investigated to explore if its inhibitory effect can be turned on and off by light. By irradiating (Z)‐axitinib in vitro with UV light, it is possible to switch it almost quantitatively to the E isomer and completely restore the biological activity of (E)‐axitinib.