Sequence (linear): Cys-Val-2-Nal-Met The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras protein, which is commonly abnormally active in cancer. Studies have suggested that interference with certain post-translational modification processes seem to have quite a high selectivity for targeting cells displaying tumor phenotypes although the reason for this is a matter of controversy (as will be explained below). After translation, RAS goes through four steps of modification: isoprenylation, proteolysis, methylation and palmitoylation. Isoprenylation involves the enzyme farnesyltransferase (FTase) transferring a farnesyl group from farnesyl pyrophosphate (FPP) to the pre-RAS protein. Also, a related enzyme geranylgeranyltransferase I (GGTase I) has the ability to transfer a geranylgeranyl group to K and N-RAS (the implications of this are discussed below). Farnesyl is necessary to attach RAS to the cell membrane. Without attachment to the cell membrane, RAS is not able to transfer signals from membrane receptors (Reuter et al., 2000). [edit]Development of FTIs After a program of high-throughput screening of a class of drugs targeting the first step, the farnesyltransferase inhibitors (FTIs) were developed (Reuter et al., 2000). A number of molecules were found to have FTI activity. Some earlier compounds were found to have major side effects, and their development was discontinued. The others have entered clinical trials for different cancers. SCH66336 (Ionafarnib) was the first to do so, followed by R115777 (Zarnestra, Tipifarnib) (Caponigro et al., 2003). Unfortunately, the predicted ''early potential [of FTIs] has not been realised (Downward J, 2003). The anti-tumor properties of FTIs were attributed to their action on RAS processing, however this assumption has now been questioned. Of the three members (H, N and K) of the RAS family, K-RAS is the form found most often mutated in cancer. As noted above, as well as modification by FFTase an alternative route to creation of biologically active RAS is through GGTase modification. When FFTase becomes blocked by FFTase inhibitors this pathway comes in to operation - both K and N-RAS are able to be activated through this mechanism. In recognition of this a joint administration of FTIs and GTIs was tried, however this resulted in high toxicity. It is in fact thought that the lack of FTI toxicity may be due to a failure to fully inhibit RAS: FTIs actually target normal cells but alternative pathway allow these cells to surive (Downward J, 2003). Storage and Stability: Lyophilized powder may be stored at 4C for short-term only. Stable for 12 months at -20C. Reconstitute to nominal volume (see reconstitution instructions for peptides) and store at -20C. For maximum recovery of product, centrifuge the original vial prior to removing the cap. Further dilutions can be made in assay buffer.
Purity:
95+% HPLC, Mass Spec
Form:
Supplied as a white to off-white lyophilized powder.
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