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RESEARCH PRODUCT
Synthesis and biological evaluation of cycloalkylidene carboxylic acids as novel effectors of Ras/Raf interaction.
Ilse ZündorfGerd DannhardtTheodor DingermannAnke FrieseThomas WincklerKatja Hell-momenisubject
MAPK/ERK pathwayMagnetic Resonance SpectroscopyCarboxylic acidSaccharomyces cerevisiaeAmino Acid MotifsCarboxylic AcidsAnti-apoptotic Ras signalling cascadeTwo-Hybrid System TechniquesDrug DiscoveryHumansHRASProtein kinase Achemistry.chemical_classificationbiologyChemistryKinasebiology.organism_classificationProtein Structure TertiaryProto-Oncogene Proteins c-rafBiochemistryModels ChemicalMutationMutagenesis Site-Directedras ProteinsMolecular MedicineSignal transductionPlasmidsProtein Bindingdescription
The protooncogenes Ras and Raf play important roles in signal transduction pathways regulated by mitogen-activated protein kinases. Mutations of Ras that arrest the protein in its active state are frequently implicated in tumor formation. We used Ras and Raf proteins in the yeast two-hybrid system to search for natural or synthesized substances capable of modulating Ras/Raf interaction by specifically binding to one of the interacting partners. We found that cycloalkylidene carboxylic acids enhanced Ras/Raf interaction by acting on the cysteine-rich domain of Raf. Several analogues of the active substance 2-cyclohexylidene propanoic acid were synthesized and the importance of the semicyclic double bond in the stabilization of Ras/Raf interaction was demonstrated. Variation of the size and the substituents of the cyclic system as well as the length of the carboxylic acid resulted in enhanced Ras/Raf interaction.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2002-02-28 | Journal of medicinal chemistry |