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. Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... This page is a candidate for speedy deletion. ... In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ...

Background

Studies have suggested that interference with certain post-translational modification processes seem to have quite a high selectivity for targeting cells displaying tumour phenotypes although the reason for this is a matter of controversy (as will be explained below). Tumor (American English) or tumour (British English) originally means swelling, and is sometimes still used with that meaning. ... The phenotype of an individual organism is either its total physical appearance and constitution, or a specific manifestation of a trait, such as size or eye color, that varies between individuals. ...

After translation, RAS goes through four steps of modification: isoprenylation, proteolysis, methylation and palmitoylation. Isoprenylation involves the enzyme farnesyltransferase (FFTase) 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). Prenylation or isoprenylation is the addition of hydrophobic molecules to a protein to facilitate its attachment to the cell membrane. ... Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion. ... Methylation is a term used in the chemical sciences to denote the attachment or substitution of a methyl group on various substrates. ... Palmitoylation is the covalent attachment of fatty acids to cysteine residues of membrane proteins [1] ^ Linder, M.E. (2000). ... This page is a candidate for speedy deletion. ... Farnesol is a natural organic compound which is a sesquiterpene alcohol found as a colorless liquid. ... Geranylgeranyltransferase type 1 or simply geranylgeranyltransferase is one of the three enzymes in the prenyltransferase group. ...

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). It has been suggested that Virtual_high_throughput_screening be merged into this article or section. ... Oral medication A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. ...

Unfortunately, the predicted “early potential [of FTIs] has not been realised” (Downward J, 2003). The anti-tumour 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).

Explaining success

So how to explain the preclinical successes showing that many N- or K-RAS transformed cell lines (and even tumor cell lines that do not harbor RAS mutations) are sensitive to FTase inhibitors? It has been suggested that this is due to inhibition of farnesylation of a number of other proteins (Reuter et al., 2000). Therefore it is hoped that FTIs, whilst not RAS specific, still have potential for cancer therapy.

Investigation of FTIs for alternative uses

FTIs and protozoan parasites

FTIs can also be used to inhibit farnesylation in parasites such as Trypanosoma brucei (African sleeping sickness) and Plasmodium falciparum (malaria). Interestingly, these parasites seem to be more vulnerable to inhibition of Farnesyltransferase than humans, even though the drugs tested selectively target human FTase. In some cases the reason for this may be the parasites lack Geranylgeranyltransferase I. This vulnerability may pave the way for the development of selective, low toxicity, FTI based anti-parasitic drugs 'piggybacking' on the development of FTIs for cancer research. Trypanosoma brucei is a species of parasitic protozoan trypanosomes. ... Sleeping sickness or African trypanosomiasis is a parasitic disease in humans. ... Binomial name Plasmodium falciparum Welch, 1897 Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. ... Malaria is a vector-borne infectious disease that is widespread in tropical and subtropical regions. ... Geranylgeranyltransferase type 1 or simply geranylgeranyltransferase is one of the three enzymes in the prenyltransferase group. ...

Use with Progeria

Recently studies have been published indicating that farnesyltransferase inhibitors can act to reverse instability of nuclear structure due to the genetic mutation of the LMNA gene. It is being tested as a potential drug treatment in children suffering from Hutchinson-Gilford Progeria Syndrome. Progeria narrowly refers to Hutchinson-Gilford Progeria syndrome, but the term is also used more generally to describe any of the so-called accelerated aging diseases. The word progeria is derived from the Greek for prematurely old. Because the accelerated aging diseases display different aspects of aging, but never every...

References

• Caponigro F, Casale M, Bryce J. (2003). "Farnesyl transferase inhibitors in clinical development". Expert Opin Investig Drugs. 12:943-54
• Downward J. (2003). "Targeting the RAS Signalling Pathway in Cancer Therapy". Nat Rev Cancer, 3:11-22
• Reuter WM, Morgan MA, Bergmann L. (2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?"
• Farnesyltransferase Inhibitors and Their Role in the Treatment of Multiple Myeloma
• (2006)"The latest exciting news: FTI's - a potential drug treatment for children with Progeria."
• Eastman, Richard T., Buckner, Frederick S., et al., (2006) Fighting parasitic disease by Blocking Protein Farnesylation, Journal of Lipid Research, 47, 233-240.