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 tumour phenotypes, although the reason for this is a matter of controversy.
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]
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).
It has been suggested that 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 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.
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 can also be used to inhibit farnesylation in parasites [5] such as Trypanosoma brucei (African sleeping sickness) and Plasmodium falciparum (malaria). 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.
Studies have been published indicating that farnesyltransferase inhibitors such as lonafarnib a synthetic tricyclic derivative of carboxamide with antineoplastic properties can reverse instability of nuclear structure due to the genetic mutation of the LMNA gene. The drug has been used to treat children suffering from Hutchinson–Gilford progeria syndrome. [6] Results of the first-ever clinical drug trial for children with progeria, demonstrated the efficacy of a farnesyltransferase inhibitor (FTI). [7]
| Name | Code | Description | CAS number |
|---|---|---|---|
| Chaetomellic acid A | sc-221420 | Chaetomellic acid A is a potent inhibitor of farnesyltransferase in isolated enzyme assays (IC50 = 55nM) but it is inactive in whole cells. | 148796-51-4 |
| Clavaric acid | |||
| FPT Inhibitor I | sc-221625 | FPT Inhibitor I is a highly selective and potent inhibitor of farnesyltransferase. FPT Inhibitor I exhibits inhibition of GGTase I and II at much higher concentrations. | |
| FPT Inhibitor II | sc-221626 | FPT Inhibitor II is a potent, selective farnesyltransferase and Ras farnesylation inhibitor in whole cells. | |
| FPT Inhibitor III | sc-221627 | FPT Inhibitor III is a cell-permeable farnesyltransferase inhibitor and prevents Ras processing in cells. | |
| FTase Inhibitor I | sc-221632 | FTase Inhibitor I is a potent, cell-permeable, selective, peptidomimetic inhibitor of farnesyltransferase (FTase). | 149759-96-6 |
| FTase Inhibitor II | sc-221633 | FTase Inhibitor II is a potent farnesyltransferase inhibitor that has been shown to prevent Ras activity. | 156707-43-6 |
| FTI-276 trifluoroacetate salt | sc-215057 | A highly potent RasCAAX peptidomimetic which antagonizes both H and K-Ras oncogenic signaling. This compound inhibits farnesyltransferase (Ftase) in vitro with an IC50 of 500 pM. Used as an anti-cancer agent. | 170006-72-1 (non-salt) |
| FTI-277 trifluoroacetate salt | sc-215058 | FTI-277 trifluoroacetate salt is an inhibitor of farnesyltransferase that displays antagonistic activity towards both H- and K-Ras oncogenic signaling. | 170006-73-2 (free base) |
| GGTI-297 | sc-221672 | GGTI-297 is a potent, cell-permeable, and selective peptidomimetic inhibitor of GGTase I compared to farnesyltransferase (FTase). | |
| L-744,832 Dihydrochloride | sc-221800 | L-744,832 Dihydrochloride is a Ras farnesyltransferase and p70 S6 kinase inhibitor. L-744,832 Dihydrochloride has been shown to induce tumor regression and apoptosis. | 1177806-11-9 (free acid) |
| Lonafarnib | SCH66336 | 193275-84-2 | |
| Manumycin A | sc-200857 | Manumycin A is an antibiotic generated by Streptomyces parvulus that acts as a selective and vigorous inhibitor of Ras farnesyltransferase and IKKβ. | 52665-74-4 |
| Tipifarnib | sc-364637 | Tipifarnib has been shown to inhibit farnesyltransferase and therefore the kappa B-Ras peptide. Tipifarnib has also been shown to increase apoptosis in certain cancerous cell lines. | 192185-72-1 |
| Gingerol | Gingerol shown to activate SERCA (cardiac and skeletal SR Ca2+-ATPase) with apoptosis inducing, anti-inflammatory, and antioxidant characteristics. | 23513-14-6 | |
| Gliotoxin | sc-201299 | Gliotoxin is a toxic epipolythiodioxopiperazine metabolite shown to be an immunosuppressive mycotoxin. Displays a capacity to induce apoptosis and inhibit NF-κB activation. | 67-99-2 |
| α-hydroxy Farnesyl Phosphonic Acid | sc-205200 | α-hydroxy Farnesyl Phosphonic Acid is a competitive inhibitor of farnesyltransferase and blocks Ras processing. | 148796-53-6 |
Lipid-anchored proteins are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilayer structure of the membrane alongside the similar fatty acid tails. The lipid-anchored protein can be located on either side of the cell membrane. Thus, the lipid serves to anchor the protein to the cell membrane. They are a type of proteolipids.
Progeria is a specific type of progeroid syndrome called Hutchinson-Gilford syndrome. Progeroid syndromes are a group of diseases with premature aging. Patients born with progeria typically live to an age of mid-teens to early twenties.
Ras is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours.
Prenylation is the addition of hydrophobic molecules to a protein or chemical compound. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to lipid anchors like the GPI anchor, though direct evidence of this has not been observed. Prenyl groups have been shown to be important for protein–protein binding through specialized prenyl-binding domains.
Farnesyltransferase is one of the three enzymes in the prenyltransferase group. Farnesyltransferase (FTase) adds a 15-carbon isoprenoid called a farnesyl group to proteins bearing a CaaX motif: a four-amino acid sequence at the carboxyl terminus of a protein. Farnesyltransferase's targets include members of the Ras superfamily of small GTP-binding proteins critical to cell cycle progression. For this reason, several FTase inhibitors are undergoing testing as anti-cancer agents. FTase inhibitors have shown efficacy as anti-parasitic agents, as well. FTase is also believed to play an important role in development of progeria and various forms of cancers.
Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and intellectual disabilities, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet. Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart defects, and overgrowth of the heart muscle. Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature and many have reduced levels of growth hormones. It is a RASopathy.
Geranylgeranyltransferase type 1 or simply geranylgeranyltransferase is one of the three enzymes in the prenyltransferase group. In specific terms, Geranylgeranyltransferase adds a 20-carbon isoprenoid called a geranylgeranyl group to proteins bearing a CaaX motif: a four-amino acid sequence at the carboxyl terminal of a protein. Geranylgeranyltransferase inhibitors are being investigated as anti-cancer agents.
Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.
Laminopathies are a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. They are included in the more generic term nuclear envelopathies that was coined in 2000 for diseases associated with defects of the nuclear envelope. Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals.
Geranylgeranylation is a form of prenylation, which is a post-translational modification of proteins that involves the attachment of one or two 20-carbon lipophilic geranylgeranyl isoprene units from geranylgeranyl diphosphate to one or two cysteine residue(s) at the C-terminus of specific proteins. Prenylation is thought to function, at least in part, as a membrane anchor for proteins.
Lonafarnib, sold under the brand name Zokinvy, is a medication used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in people one year of age and older.
In enzymology, a geranyltranstransferase is an enzyme that catalyzes the chemical reaction
Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha is an enzyme that in humans is encoded by the FNTA gene.
Protein farnesyltransferase subunit beta is an enzyme that in humans is encoded by the FNTB gene.
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. Both leptin and insulin recruit PI3K signalling for metabolic regulation. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.
mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.
Said Sebti (Arabic: سيد سبتي, (first name is an American cancer researcher who is Professor and Chairman of the Department of Drug Discovery at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fl. Sebti is noted for his work to rehabilitate the 'failed' cancer drug Triciribine, now under development at the pharmaceutical company Prescient Therapeutics. Sebti is currently Chief Scientific Officer at Prescient Therapeutics.
Triciribine is a cancer drug which was first synthesized in the 1970s and studied clinically in the 1980s and 1990s without success. Following the discovery in the early 2000s that the drug would be effective against tumours with hyperactivated Akt, it is now again under consideration in a variety of cancers. As PTX-200, the drug is currently in two early stage clinical trials in breast cancer and ovarian cancer being conducted by the small molecule drug development company Prescient Therapeutics.