1. Synthesis and biological evaluation of cycloalkylidene carboxylic acids as novel effectors of Ras/Raf interaction
- Author
-
Ilse Zündorf, Gerd Dannhardt, Theodor Dingermann, Anke Friese, Thomas Winckler, and Katja Hell-Momeni
- Subjects
MAPK/ERK pathway ,Magnetic Resonance Spectroscopy ,Carboxylic acid ,Saccharomyces cerevisiae ,Amino Acid Motifs ,Carboxylic Acids ,Anti-apoptotic Ras signalling cascade ,Two-Hybrid System Techniques ,Drug Discovery ,Humans ,HRAS ,Protein kinase A ,chemistry.chemical_classification ,biology ,Chemistry ,Kinase ,biology.organism_classification ,Protein Structure, Tertiary ,Proto-Oncogene Proteins c-raf ,Biochemistry ,Models, Chemical ,Mutation ,Mutagenesis, Site-Directed ,ras Proteins ,Molecular Medicine ,Signal transduction ,Plasmids ,Protein Binding - Abstract
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.
- Published
- 2002