Fpp

FIGURE 9.30 Ternary complex formed by tifiparnib, FPP and FTase.

Phe-360P

FIGURE 9.30 Ternary complex formed by tifiparnib, FPP and FTase.

adopts a U shape by van der Waals stacking between the cyanophenyl and piperazine units, with the imidazole unit occupying the apex of the structure and coordinating with the zinc cation. In FTase, FPP binds adjacently at the corresponding site, with the pyrophosphate group occupying a positively charged pocket (Fig. 9.31A). However, in GGTase I the inhibitor does not form a ternary complex with geranylgeraniol pyrophosphate and instead it occupies the lipid substrate binding pocket and a portion of the peptide substrate binding pocket. The cationic site is occupied by a sulphate anion, which is placed where the pyrophosphate of GGPP normally binds (Fig. 9.31B).115

5.2.3. Bisubstrate analogues

Some FTase inhibitors incorporate structural motifs from both FPP and the CAAX sequence. One example is compound 9.3, where the thiol moiety of CAAX was substituted by a carboxylic group and the farnesyl chain was covalently attached to the peptide through an amide linkage.

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