2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach

Schehr, Miriam; Ianes, Chiara; Weisner, Jörn; Heintze, Linda; Müller, Matthias; Pichlo, C.; Charl, Julia; Brunstein, Elena; Ewert, Julia; Lehr, Marc; Baumann, Ulrich; Rauh, Daniel; Knippschild, Uwe; Peifer, Christian; Herges, Rainer

doi:10.1039/c9pp00010k

Cited by 54 publications

(68 citation statements)

References 52 publications

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“…Since cis-isomer is more prone to reduction than the trans-isomer, the active hydrazine was present in higher concentration in the irradiated sample, explaining the observed higher potency. 82 Again, using a more electron rich, N-methyl-imidazole-based analogue 87 prevented the reduction, highlighting the feasibility of this approach.…”

Section: Stability In Water and In The Cellular Environmentmentioning

confidence: 99%

Photoresponsive molecular tools for emerging applications of light in medicine

et al. 2020

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Section: Stability In Water and In The Cellular Environmentmentioning

confidence: 99%

Photoresponsive molecular tools for emerging applications of light in medicine

et al. 2020

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“…Overexpression and purification of GST-CK1δ fusion proteins, either wild type or mutant, were performed as described previously [38].…”

Section: Expression and Purification Of Gst Fusion Proteinsmentioning

confidence: 99%

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

Liu

Witt

Ianes

et al. 2019

IJMS

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Protein kinases of the CK1 family can be involved in numerous physiological and pathophysiological processes. Dysregulated expression and/or activity as well as mutation of CK1 isoforms have previously been linked to tumorigenesis. Among all neoplastic diseases, colon and rectal cancer (CRC) represent the fourth leading cause of cancer related deaths. Since mutations in CK1δ previously found in CRC patients exhibited increased oncogenic features, inhibition of CK1δ is supposed to have promising therapeutic potential for tumors, which present overexpression or mutations of this CK1 isoform. Therefore, it is important to develop new small molecule inhibitors exhibiting higher affinity toward CK1δ mutants. In the present study, we first characterized the kinetic properties of CK1δ mutants, which were detected in different tumor entities. Subsequently, we characterized the ability of several newly developed IWP-based inhibitors to inhibit wild type and CK1δ mutants and we furthermore analyzed their effects on growth inhibition of various cultured colon cancer cell lines. Our results indicate, that these compounds represent a promising base for the development of novel CRC therapy concepts.

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“…However, previously reported photoswitchable small molecule kinase inhibitors ( Figure 1 ) exhibited only slight differences in the biological activity between the metastable, irradiated, and the thermodynamically stable state [ 9 ]. These examples include three azobenzene-based kinase inhibitors with a 1.6- to 11-fold difference in biological activities upon photoswitching [ 10 , 11 , 12 ] and a protein kinase C inhibitor based on a diarylethene-like maleimide showing a higher difference with a factor of 26, but no reversible switching in aqueous solutions (similar to axitinib ( 1 ), see next paragraph) [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

Heintze

Schmidt

Rodat

et al. 2020

IJMS

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In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.

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2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach

Abstract: The synthesis and characterization of new photoswitchable kinase inhibitors is reported.

Cited by 54 publications

References 52 publications

Photoresponsive molecular tools for emerging applications of light in medicine

Photoresponsive molecular tools for emerging applications of light in medicine

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

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

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