Sch226374

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

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment