J T

FIGURE 9.28 Farnesylation of Ras.

a and p sub-units that binds to the 'CAAX box' of the Ras protein, which adopts an extended conformation with the cysteine sulphur coordinated to the zinc ion in the active site. This coordination apparently lowers the pKa of the thiol, increasing the local concentration of thiolate anion and facilitating its farnesylation (Fig. 9.28) Design of inhibitors of this enzyme has been achieved using three approaches:105-107

a. Analogues that compete with the substrate, farnesyl pyrophosphate (FPP).

b. Peptide or non-peptide peptidomimetic compounds targeted at the terminal CAAX sequence of Ras.

c. Bisubstrate analogues that combine both structural features.

5.2.1. FPP mimics

This class of inhibitors has attracted less interest because of their potential lack of selectivity due to the fact that FPP is a substrate for other enzymes such as squalene synthase. Although some of these compounds (e.g. 9.1 and 9.2) are potent inhibitors of the enzyme, they have failed to show in vivo activity.

5.2.2. Peptides and peptidomimetics that mimic the CAAX motif

Initial reports about the FTase inhibitory activity of CAAX tetrapeptides led to the identification of Cys-Val-Phe-Met as a lead for systematic structural modification. Most of these analogues were aimed at achieving suitable pharmacokinetic properties while retaining the thiol group, important for coordination to zinc. Some of the changes consisted of replacing the labile peptide bonds by stable methyle-namino or methylenoxy links (e.g. L-739750) or the use of non-proteinogenic

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