Fig. 6. Antitumor activity of FTI-276 and FTI-2153.

block the processing of H-Ras in NIH-3T3 cells with an IC50 of 10 nM but had no effect on the geranylgeranylation of RaplA at concentrations over 3 |M The corresponding imidazole-aminomethylene-leucine derivative 22 was also prepared and showed potent inhibition ofGGTase I with little effect on FTase (37). Again, the selective inhibition was carried over into whole cell experiments with the methyl ester derivative 23 blocking the geranylgeranylation of RaplA at nM level concentrations with little effect on the farne-sylation of H-Ras at much higher concentrations.

3.5. Focused Combinatorial Libraries for the Discovery of Cysteine Replacements

A second strategy for the identification of noncysteine N-termini for the biphenyl-derivedpeptidomimetics involvedthe use ofa focusedcombinatorial library (36). Amide coupling to Wang resin-linked amine 24 provided a series of nonthiol structures from which nicotinamide 25 rapidly emerged as a promising lead (Fig. 6; Table 6). Reduction of the amide bond and retro-inversion provided 3-aminopyridine derivative 29 and the corresponding ether 30, which were 10-fold and 20-fold more active than the original amide 25. The pyridine nitrogen appears to participate in a critical interaction, perhaps with the active-site zinc, because positional isomers 26 and 27 and phenyl-derivative 31 (38) were significantly less active. Interestingly, the pyridine-derived inhibitors were essentially devoid of activity against GGTase I (IC50 > 10 |M for 25-37).

Table 6

Farnesyltransferase Inhibitors Incorporating an N-Terminal Pyridine





in vitro ic50 (nM)


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