Phosphinyl acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase
| Autor: | Dinesh V. Patel, Eric M. Gordon, Robert J. Schmidt, Harold N. Weller, Marian G. Young, Robert Zahler, Mariano Barbacid, Joan M. Carboni, Johnni L. Gullo-Brown, Lisa Hunihan, Carol Ricca, Simon Robinson, Bernd R. Seizinger, Anne V. Tuomari, Veeraswamy Manne |
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| Rok vydání: | 1995 |
| Předmět: |
chemistry.chemical_classification
Farnesyl-diphosphate farnesyltransferase Alkyl and Aryl Transferases Farnesyl Protein Transferase biology Chemistry Stereochemistry Swine Farnesyl pyrophosphate Rational design Brain Tripeptide 3T3 Cells Phosphinic Acids Substrate Specificity chemistry.chemical_compound Mice Enzyme Enzyme inhibitor Transferases Drug Discovery biology.protein Molecular Medicine Transferase Animals |
| Zdroj: | Journal of medicinal chemistry. 38(3) |
| ISSN: | 0022-2623 |
| Popis: | The rational design, synthesis, and biological activity of phosphonyl- and phosphinyl-linked bisubstrate analog inhibitors of the enzyme Ras farnesyl protein transferase (FPT) are described. The design strategy for these bisubstrate inhibitors involved connection of the critical binding components of the two substrates of FPT (ras protein and farnesyl pyrophosphate, FPP) through a phosphonyl- or phosphinyl-bearing linker. Compound 14, the first example in this series, was found to be a potent FPT inhibitor (I50 = 60 nM). A further 15-fold enhancement in activity was observed upon replacement of the VLS tripeptide sequence in 14 with VVM (15, I50 = 6 nM). The phosphinic acid analog 16 (I50 = 6 nM) was equiactive to phosphonic acid 15. Compounds 14-16 afforded 1000-fold selectivity for FPT against the closely related enzyme geranylgeranyl protein transferase type I, GGT-I [14, I50(GGT-I) = 59 microM; 15 I50(GGT-I) = 10 microM; 16 I50(GGT-I) = 21 microM]. Methyl and POM ester prodrugs 17-19 were prepared and evaluated in whole cell assays and appear to block ras-induced cell transformation, as well as colony formation in soft agar. A distinctive feature of this novel class of potent and selective bisubstrate FPT inhibitors is that they are non-sulfhydryl in nature. |
| Databáze: | OpenAIRE |
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