0000000000681198

AUTHOR

Christoph Schächtele

showing 2 related works from this author

Profile and molecular modeling of 3-(indole-3-yl)-4-(3,4,5-trimethoxyphenyl)-1 H-pyrrole-2,5-dione (1) as a highly selective VEGF-R2/3 inhibitor.

2006

We report on selectivity profiling of 1 in a panel of 20 protein kinases and molecular modeling indicating 1 to be highly active and selective for VEGF-R2/3. Sequence alignment analysis and detailed insights into the ATP binding pockets of targeted protein kinases from the panel result in a unique structural architecture of VEGF-R2 mainly caused by the hydrophobic pocket I, determining the molecular basis for activity and selectivity of 1.

Indole testModels MolecularBinding SitesIndolesMolecular modelStereochemistryChemistryKinaseMolecular Sequence DataBiological activitySequence alignmentCrystallography X-RayVascular Endothelial Growth Factor Receptor-3Vascular Endothelial Growth Factor Receptor-2Drug DiscoveryMolecular MedicinePyrrolesAmino Acid SequenceBinding siteSelectivityPeptide sequenceHydrophobic and Hydrophilic InteractionsJournal of medicinal chemistry
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Design, Synthesis, and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors

2006

The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 microM and reduced angiogenesis in the in vivo chick embryo model. Interestingly, in a series of 2,3-diarylmaleimides closely related to this lead, no other compound was found to be active in the tubulin polymerization assay. However, by screening in the in vivo chick embryo assay 10 was identified as a potent angiogenesis inhibitor indicating an alternative target. Indeed, molecular modeling studies suggest a reasonable binding mode of 10 at the ATP-binding site of the model kinase CDK2. Motivated by these results, analogues of 10 were screened for inhibitory activity in…

Models MolecularIndolesanimal structuresAngiogenesisAngiogenesis InhibitorsChick EmbryoIn Vitro TechniquesMaleimidesStructure-Activity Relationshipchemistry.chemical_compoundAdenosine TriphosphateIn vivoDrug DiscoveryAnimalsStructure–activity relationshipPyrrolesBinding siteCombretastatinBinding SitesbiologyChemistryKinaseCyclin-dependent kinase 2Vascular Endothelial Growth Factor Receptor-2Angiogenesis inhibitorBiochemistryDrug Designbiology.proteinMolecular MedicineJournal of Medicinal Chemistry
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