Strategies For The Discovery Of Inhibitors

FTase is a bisubstrate (FPP and p21-Ras protein) enzyme. Among various possible strategies, the inhibition of its activity may be achieved with compounds able to mimic and (or) to compete with either FPP or p21-Ras proteins.

3.1. Rationale Design of "CAAX" Mimic p21-Ras Competitive Inhibitors

The discovery, that some p21 Ras CAAX tetrapeptides (3) inhibit FTase, stimulated intensive rational drug design ofCAAX mimics leading to peptidic (15-17), pseudopep-tidic and peptidomimetic inhibitors (18-25). Although some of these compounds were found tobe active both in cellular and in animal models (26-29), only recently have some of these reached early clinical trials.

Our contribution to the design ofp21-Ras-competitive inhibitors ofFTase startedwith molecular modeling studies of CVFM peptide analogs (Fig. 1; I/1) using molecular modeling dynamics and energy minimization (16). These studies demonstrated a direct correlation between FTase inhibitory activity and the proclivity of the inhibitors to adopt an extended conformation with CaCys-CaMet distance >7.5 Á. This prompted us to search for hydrophobic scaffolds able to orientate the cysteine and methionine units according to apharmacophore model derived from the potent prototype Cys-(N-Me)Val-Tic-Met (22) (Fig. 1; I/2). We intentionally restricted this search to scaffolds that were unable to access low-energy turn conformations. The 1,5-naphthyl scaffold proved to be worthy of further investigation (Fig. 2; I/3) (25). It satisfies the distance requirement between Cys and Met units and also provides a rigid template that directs these units

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