FTase inhibitors

Fig. 1. FTase inhibitors in which amide bonds were replaced by isosteric amines and ethers, and which incorporate non-natural amino acids...

However, 2 also affected the regulation of actin stress fiber formation [19]. Rho proteins are involved in the regulation of various cytoskeletal structures, and RhoB is believed to be one of the prime targets of FTase inhibitors. Rho B is apparently both geranylgeranylated and farnesylated [20, 21]. If cells were treated with 2, vesicular localization of Rho B was inhibited. Thus 2 may also inhibit the farnesylation of Rho B, thereby interfering with actin stress fiber formation [22]. 

The design of FTase inhibitors based on the structure of farnesyl pyrophosphate has been pursued with less intensity due to the possible nonselective effects of competing with other enzymes such as squalene synthetase that also accept farnesylpyrophosphate as substrate [3,4,9,10-12]. 

In particular, a series of completely non-peptidic nonsulfhydryl FTase inhibitors 22 and 23 was uncovered (Fig. 6). 

Fig. 6. FTase inhibitors identified from compound libraries...

Although FTase inhibitors influence the farnesylation of Ras they are likely to interfere with the posttranslational modifications of other CAAX-containing proteins as well. Apart from the approximately 20 farnesylated proteins that are known today, farnesylation is also required for normal Ras function which in turn is critical for normal cell viability. For these reasons farnesyltransferase... 

These findings have raised questions of which additional proteins are the molecular targets of FTase inhibitors. One class of candidates involves members... 

The is-olefin was prepared as a trans-amide bond replacement. A number of compounds incorporating substituents to mimic both natural and unnatural amino acid sidechains were prepared by adapting chemistry developed by Ibuka for the synthesis of Zs-olefin peptide isosteres (see Scheme l).40,41 The key step involved anti-SN2 displacement of vinyl mesylate 8 by boron trifluoride-activated cuprate addition. Compounds containing butyl, propyl, and benzyl substituents at the allylic positions to mimic the aj and sidechains produced potent FTase inhibitors (Table 4). 

Table 14. Effect of N-Acylpiperazine FTase Inhibitors on Anchorage Independent Growth of ras- and raf-Transformed Cells...

Table 20. Inhibition of Wild Type and aPR202A FTase by Carboxyl-Containing and Non-Carboxyl-Containing FTase Inhibitors...

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