From pure FPP to mixed FPP and CAAX competitive inhibitors of farnesyl protein transferase

• Published in: Bioorganic & medicinal chemistry letters 2003-04, Vol.13 (8), p.1459-1462
• Main Authors: Lannuzel, Marc, Lamothe, Marie, Schambel, Philippe, Etiévant, Chantal, Hill, Bridget, Perez, Michel
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - metabolism; Animals; Antineoplastic agents; Binding, Competitive; Biological and medical sciences; Cattle; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Humans; Inhibitory Concentration 50; Medical sciences; Membrane Proteins - chemistry; Models, Molecular; Pharmacology. Drug treatments; Polyisoprenyl Phosphates - chemistry; Polyisoprenyl Phosphates - pharmacology; Protein Prenylation - drug effects; ras Proteins - drug effects; ras Proteins - metabolism; Sesquiterpenes; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00171-9

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. Compound 3c was prepared and identified as a powerful inhibitor of FPTase, partially competitive versus FPP and fully competitive versus dansyl-GCVLS.