Farnesyltransferase inhibitor
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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.
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).
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.[1]
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.[1] One FTI found in the screening was clavaric acid, a mushroom isolate. 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 (Lonafarnib) was the first to do so, followed by R115777 (Zarnestra, Tipifarnib).[2]
Unfortunately, the predicted “early potential [of FTIs] has not been realised”.[3] 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 is blocked by FFTase inhibitors this pathway comes into 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 survive (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.[1] Therefore it is hoped that FTIs, whilst not Ras specific, still have potential for cancer therapy.
Products in Development
Investigation of FTIs for alternative uses
Alzheimer's disease
LNK-754 inhibits the activity of a protein called farnesyl-transferase (FT). This class of molecules are called FTIs (or farnesyl-transferase inhibitors). As with mTOR inhibitors, many companies developed them to treat cancers, where they were unsuccessful. The mechanism by which FTIs work is through inhibition of this enzyme, which adds a fatty acid molecule to proteins (such as the oncogene, or cancer-generating, ras). Many proteins can exist in a cell in various locations, and the addition of a farnesyl group targets proteins to the plasma membrane. When ras gets to the plasma membrane, it becomes activated, and leads to tumour formation if this process is not stopped. It was thought that by inhibiting FT, ras will not be activated, therefore preventing cancer growth. The problem was that ras can also be modified by other mechanisms, and thus FTIs were not sufficient to inhibit malignant growth induced by ras signaling.
Most FTIs also have side effects (since they also indirectly affect mTOR), and their development for HD would likely not be successful. However, the remarkable finding is that Link Medicine has developed an FTI which does NOT affect mTOR signaling. This is a novel and important molecule, and might have higher probability to be of use for long term chronic diseases such as HD.
However, as with any new approach, it is too early yet to see if it will be safe in longer trials, and effective in people. But there is much room for hope, as this represents a completely novel mechanism to evaluate in people. If autophagy mechanisms in humans are similar as those of mice, then there is much reason for optimism. Lets hope for continued success for Link Medicine, so that it will be safe and the lead molecule progresses to the stage of being tested in HD subjects[4]
FTIs and protozoan parasites
FTIs can also be used to inhibit farnesylation in parasites[5] 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.
Use in 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.[6]
References
- ^ a b c Reuter CW, Morgan MA, Bergmann L (2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?". Blood. 96 (5): 1655–69. PMID 10961860.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ 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
- ^ Link Medicine: Exploring a new mechanism for neurodegeneration
- ^ Eastman RT, Buckner FS, Yokoyama K, Gelb MH, Van Voorhis WC (2006). "Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation". J. Lipid Res. 47 (2): 233–40. doi:10.1194/jlr.R500016-JLR200. PMID 16339110.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Mehta IS, Bridger JM, Kill IR (2010). "Progeria, the nucleolus and farnesyltransferase inhibitors". Biochem. Soc. Trans. 38 (Pt 1): 287–91. doi:10.1042/BST0380287. PMID 20074076.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
Anuj G. Agrawal and Rakesh R. Somani (2011). Farnesyltransferase Inhibitor in Cancer Treatment, Current Cancer Treatment - Novel Beyond Conventional Approaches, Öner Özdemir (Ed.), ISBN 978-953-307-397-2, InTech, Available from: http://www.intechopen.com/articles/show/title/farnesyltransferase-inhibitor-in-cancer-treatment