Farnesyl Diphosphate-Based Inhibitors of Ras Farnesyl Protein Transferase

Article abstract of DOI:10.1021/jm00015a013

The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described.Compound 3, wherein a β-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 μM) and mevalonate kinase (I50(MK) = >200 μM).A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken.Both the carboxylic and phosphonic acid groups of the β-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 μM).The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 μM), substitution by a dodecyl fragment (14, I50 = 9 μM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 μM).Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 μM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM).FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.