Design, Synthesis, and Characterization of a Photoactivatable Caged Prodrug of Imatinib

Zindler, Melanie; Pinchuk, Boris; Renn, Christian; Horbert, Rebecca; Döbber, Alexander; Peifer, Christian

doi:10.1002/cmdc.201500163

Cited by 30 publications

(24 citation statements)

References 34 publications

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“…Our research group has already evaluated caged derivatives of the approved kinase inhibitors vemurafenib [30] and imatinib [47] in vitro . To the best of our knowledge, there are no caged VEGFR-2 inhibitors described so far.…”

Section: Discussionmentioning

confidence: 99%

Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors

et al. 2016

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Abstract:In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.

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Section: Discussionmentioning

confidence: 99%

Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors

et al. 2016

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“…Most of these inhibitors are caged prodrugs, that is, kinase inhibitors modified with a photoremovable protecting group that can be irreversibly cleaved by light . In line with this notion, our group has published photoactivatable prodrugs of the approved kinase inhibitors vemurafenib and imatinib in the past few years. A drawback of the caging approach is that activation remains irreversible and involves the release of a by‐product upon uncaging.…”

Section: Introductionmentioning

confidence: 96%

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

et al. 2018

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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.

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“…A relatively new group of cancer therapeutics are protein kinase inhibitors (PKI), which are primarily used in individualized therapy. [101] The work of Peifer and co-workers [102] recently focused on the development of photoactivatable PKIs, including imatinib [103] and vemurafenib. [104] Imatinib highlighted.…”

Section: Protein Kinase Inhibitorsmentioning

confidence: 99%