Farnesyltransferase inhibitor
Encyclopedia
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.
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.
of a class of drugs
targeting the first step, the farnesyltransferase inhibitors (FTIs) were developed. 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).
Unfortunately, the predicted “early potential [of FTIs] has not been realised”. 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 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 survive (Downward J, 2003).
(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.
gene. It is being tested as a potential drug treatment in children suffering from Hutchinson-Gilford Progeria Syndrome
.
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
drugs that target protein farnesyltransferase
Farnesyltransferase
Farnesyltransferase is one of the three enzymes in the prenyltransferase group. Farnesyltransferase 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...
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
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
, methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
and palmitoylation
Palmitoylation
S-Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their...
. Isoprenylation involves the enzyme farnesyltransferase
Farnesyltransferase
Farnesyltransferase is one of the three enzymes in the prenyltransferase group. Farnesyltransferase 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...
(FTase) transferring a farnesyl
Farnesol
Farnesol is a natural organic compound which is an acyclic sesquiterpene alcohol found as a colorless liquid. It is insoluble in water, but miscible with oils...
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.
Development of FTIs
After a program of high-throughput screeningHigh-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
of a class of drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
targeting the first step, the farnesyltransferase inhibitors (FTIs) were developed. 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).
Unfortunately, the predicted “early potential [of FTIs] has not been realised”. 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 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 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. Therefore it is hoped that FTIs, whilst not Ras specific, still have potential for cancer therapy.FTIs and protozoan parasites
FTIs can also be used to inhibit farnesylation in parasites such as Trypanosoma bruceiTrypanosoma brucei
Trypanosoma brucei is a parasitic protist species that causes African trypanosomiasis in humans and nagana in animals in Africa. There are 3 sub-species of T. brucei: T. b. brucei, T. b. gambiense and T. b. rhodesiense.These obligate parasites have two hosts - an insect vector and mammalian host...
(African sleeping sickness) and Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
(malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
). 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 LMNALMNA
Lamin A/C also known as LMNA is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins.-Function:...
gene. It is being tested as a potential drug treatment in children suffering from Hutchinson-Gilford Progeria Syndrome
Progeria
Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
.