Bifunctional Duocarmycin Analogues as Inhibitors of Protein Tyrosine Kinases
| Autor: | Wolfgang Heydenreuter, Matjaz Humar, Lutz F. Tietze, Alexander Kreft, Stephan A. Sieber, Irmgard Merfort, Mehrnoush Kangani, Christian De Ford, Kamala Penchalaiah |
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| Rok vydání: | 2019 |
| Předmět: |
In silico
Pharmaceutical Science Aldehyde dehydrogenase 01 natural sciences Aldehyde Dehydrogenase 1 Family Analytical Chemistry chemistry.chemical_compound Duocarmycins Drug Discovery Humans Bifunctional Protein Kinase Inhibitors Duocarmycin Pharmacology biology 010405 organic chemistry Organic Chemistry In vitro toxicology Kinase insert domain receptor Vascular Endothelial Growth Factor Receptor-2 In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Complementary and alternative medicine chemistry Biochemistry Docking (molecular) biology.protein Molecular Medicine |
| Zdroj: | Journal of natural products. 82(1) |
| ISSN: | 1520-6025 |
| Popis: | Bifunctional duocarmycin analogues are highly cytotoxic compounds that have been shown to be irreversible aldehyde dehydrogenase 1 inhibitors. Interestingly, cells with low aldehyde dehydrogenase 1 expression are also sensitive to bifunctional duocarmycin analogues, suggesting the existence of another target. Through in silico approaches, including principal component analysis, structure-similarity search, and docking calculations, protein tyrosine kinases, and especially the vascular endothelial growth factor receptor 2 (VEGFR-2), were predicted as targets of bifunctional duocarmycin analogues. Biochemical validation was performed in vitro, confirming the in silico results. Structural optimization was performed to mainly target VEGFR-2, but not aldehyde dehydrogenase 1. The optimized bifunctional duocarmycin analogue was synthesized. In vitro assays revealed this bifunctional duocarmycin analogue as a strong inhibitor of VEGFR-2, with low residual aldehyde dehydrogenase 1 activity. Altogether, studies revealed bifunctional duocarmycin analogues as a new class of naturally derived compounds that express a very high cytotoxicity to cancer cells overexpressing aldehyde dehydrogenase 1 as well as VEGFR-2. |
| Databáze: | OpenAIRE |
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