Alpha-cyanocinnamide derivatives: a new family of non-peptide, non-sulfhydryl inhibitors of Ras farnesylation.
Farnesylation of Ras and other proteins is required for their membrane attachment and normal function. Here we report on the synthesis of alpha-cyanocinnamide derivatives, a new family of farnesyltransferase inhibitors. These compounds are nonpeptidic and do not contain sulfhydryl groups. The most potent compound is a pure competitive inhibitor with respect to the Ras protein and mixed competitive with respect to farnesyl diphosphate. Selectivity studies against geranylgeranyltransferase and biological activities of selected compounds are described.
Poradosu
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E
Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
Gazit
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A
Reuveni
H
H
Levitzki
A
A
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002461:Cell Line, Transformed; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051231:Farnesyltranstransferase; D011905:Genes, ras; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D013379:Substrate Specificity
D002934:Cinnamates; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase