Synthesis and biological evaluation of cycloalkylidene carboxylic acids as novel effectors of Ras/Raf interaction.
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.
Friese
Anke
A
Institut für Pharmazeutische Biologie, Universität Frankfurt/M. (Biozentrum), D-60439 Frankfurt am Main, Germany.
Hell-Momeni
Katja
K
Zündorf
Ilse
I
Winckler
Thomas
T
Dingermann
Theodor
T
Dannhardt
Gerd
G
D020816:Amino Acid Motifs; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D018631:ras Proteins / Q000378:metabolism*
D002264:Carboxylic Acids; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins