From pure FPP to mixed FPP and CAAX competitive inhibitors of farnesyl protein transferase.
Starting from a FPP analogue with nanomolar inhibitory activity against isolated FPTase, yet lacking activity in cellular assays, structural modifications were performed to enhance cellular activity by removing all acidic functionalities. Overall, these changes resulted in the transformation of a pure FPP to a mixed FPP and CAAX competitive inhibitor with nanomolar activity on isolated FPTase and micromolar inhibitory activity in the farnesylation of H-Ras in cultured DLD-1 cells.
Lannuzel
Marc
M
Department of Medicinal Chemistry 4, Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, 81106 Castres Cedex, France.
Lamothe
Marie
M
Schambel
Philippe
P
Etiévant
Chantal
C
Hill
Bridget
B
Perez
Michel
M
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D011106:Polyisoprenyl Phosphates / Q000737:chemistry* / Q000494:pharmacology*; D017368:Protein Prenylation / Q000187:drug effects; D012717:Sesquiterpenes; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011106:Polyisoprenyl Phosphates; C109563:RTL8C protein, human; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins