Lonafarnib (SCH-66336)

X-ray diffraction studies of BMS-214662 and tipifarnib complexed with farnesyl transferase show that they bind to a hydrophobic cleft formed at the interface of the a and p sub-units, forming a ternary complex with the FPP substrate and the enzyme, binding the catalytic zinc cation at the rim of the active site. Therefore, they act by a peptide-competitive mechanism.114 This interaction is exemplified in Fig. 9.30 for the case of tipifarnib, which adopts a U shape stabilized by p-stacking interactions between the two chlorophenyl rings. Other aromatic stacking interactions are important, including those between the 4-chlorophenyl unit and the farnesyl moiety, the quinoline unit and Tyr-361 p, and the 3-chlorophenyl ring and Trp-102p and Trp-106p. The imidazole nitrogen coordinates with the zinc co-factor at the catalytic centre, and water-mediated hydrogen bonds are established between the quinolone carbonyl oxygen and the Phe-360p at the protein backbone, as well as between the amino group and the FPP a-phosphate moiety. Similarly, the imidazole ring in BMS-214662 binds to the zinc cation in the active site and the union is stabilized by several p-stacking interactions.114

L-778123 was designed to selectively compete with the binding of the CAAX fragment of Ras in FTase, but in vivo studies showed that it also inhibited GGTase I in the presence of anions such as sulphate and phosphate by unexpectedly competing with the GGPP substrate rather than with the peptide. The inhibitor

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