Specific farnesyl transferase inhibitors ftis have been developed that selectively inhibit the processing of these proteins. Upon treatment of cells with ftis, some farnesylated proteins, including k and nras, become alternatively prenylated by geranylgeranyl transferase1 40, 45. Hdj2 prenylation was inhibited in 1416 patients tested, and the average inhibition of farnesyl transferase activity at 300 mgm 2 dose was 54% range 3890%. Prediction and evaluation of protein farnesyltransferase inhibition by. Effects of statins and farnesyl transferase inhibitors on erk. Farnesyl transferase inhibitors impair chromosomal. Gliotoxin is a dual inhibitor of farnesyltransferase and. Farnesyltransferase inhibitor an overview sciencedirect. Ras, rhob, pxf, rap2, and cyclic gmp phosphodiesterase. Pdf a protein farnesyl transferase involved in abscisic. Tolerability, pharmacokinetics, safety, and doselimiting toxicity were characterized. A commercially available, cell permeable, proteinfarnesyl transferase inhibitor interfered with the seruminduced morphological change in candida albicans from a cellular yeast form to a filamentous form. Several of them have recently entered clinical trials. This invention comprises the novel compounds of formula i wherein r, t, y 1, y 2, r 1, r 2, r 3, r 5, r 6 and r 7 have defined meanings, having farnesyl transferase inhibiting activity.
Free fulltext pdf articles from hundreds of disciplines, all in one place phase ii study of the farnesyl transferase inhibitor r115777 in patients with sensitive relapse smallcell lung cancer pdf paperity. Here, we observed that treatment of various cancer cell lines with the fti lonafarnib caused. Pdf farnesyl transferase is a heterodimer transferase that targets ras proteins and attaches a. Farnesyl transferase inhibitors agonists modulators. Fiveyear overall survival was 5511% and event free survival was 4111%, with no significant difference between patients who did or did not receive tipifarnib. Sch66336 is one of the first ft inhibitors to undergo clinical testing. Rpr107393 free base is a selective squalene synthase inhibitor, which inhibits rat liver microsomal squalene synthase with an ic of 50 0. Effect of a farnesyl transferase inhibitor r115777 on. Purpose to determine whether r115777 improves survival in patients with refractory advanced colorectal cancer crc in a multicenter, doubleblind, prospective randomized study.
We report a phase i trial to assess the maximum tolerated dose, toxicities, and biological. Acat catalyzes esterification of free cholesterol to cholesterol ester for incorporation in vldl in the liver and chylomicrons in the intestine and for sequestration in intracellular vesicles in macrophages, vascular smooth muscle cells and mesangial cells. Jun 18, 2002 farnesylation is a posttranslational lipid modification in which a 15carbon farnesyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins in a reaction catalyzed by protein farnesyltransferase ftase. Human protein farnesyltransferase ftase catalyzes the addition of a c15 farnesyl lipid group to the cysteine residue located in the. A farnesyl transferase inhibitor induces apoptosis of. There is a constant need to discover new targets for disease control. Farnesyl transferase inhibitors fti exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials.
Ganguly, in annual reports in medicinal chemistry, 20. Mutations in the ras family of oncogenes are common in human cancers 4, and have been associated with. Farnesyltransferase inhibitors farnesyltransferase inhibitors hahn, stephen m. Upon treatment of cells with ftis, some farnesylated proteins, including k and nras, become alternatively prenylated by geranylgeranyl transferase 1 40, 45. Fti277 trifluoroacetate salt is an inhibitor of farnesyl transferase that displays antagonistic activity towards both h and kras oncogenic signaling. Potential targets and biological modes of action of ftis are discussed, and the results of clinical trials are summarized. Pdf farnesyltransferase ft inhibitors ftis are among the first wave of signal transduction inhibitors to be clinically tested for. Previous studies have shown that product release is rate limiting and is dependent on binding of either a new peptide or isoprenoid diphosphate substrate. The present invention is directed to substituted benozdiazepine compounds which inhibit farnesylprotein transferase ftase and the farnesylation of the oncogene protein ras. Insulin stimulates the phosphorylation and activity of. Effect of a farnesyl transferase inhibitor r115777 on ductal carcinoma in.
The farnesyl transferase inhibitor fti sch66336 lonafarnib. Lonafarnib sch 66336 is a small molecule inhibitor of farnesyl transferase ftase, which adds a 15carbon farnesyl group to several gproteins important in intracellular signaling involved in cell survival, including. Polymorphism in the farnesyl diphosphate farnesyl transferase. These inhibitors prevent ras processing and membrane localization and are effective in reversing the transformed phenotype of rat1. Inhibition of ras can be accomplished through inhibition of farnesyl transferase, the enzyme responsible for this modification. Farnesyl protein transferase fptase catalyzes the first of a series of posttranslational modifications of ras required for full biological activity. The ras pathway is essential for cell growth and proliferation. By johns hopkins medicine, rxpg the new hopkins research, and similar results from other labs, shows that a class of drugs known as farnesyl transferase inhibitors, or ftis, can reverse an abnormality in laboratorygrown cells engineered to mimic cells from progeria patients. Thirty patients with solid tumors received a median of 2.
Phase iiiii trial of a pretransplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia. Farnesyltransferase is one of the three enzymes in the prenyltransferase group. No hy119257 abt100 is a potent, highly selective and orally active farnesyltransferase inhibitor. This study identified a novel association between the nafld activity score nas and the single nucleotide polymorphism snp rs2645424 in the. Farnesyltransferase and geranylgeranyltransferasei. The inhibitor has a negligible effect on the growth of c. M305733200 october 24, 2003 the journal of biological chemistry 278, 4171841727. It was not totally surprising that one of them showed activity. Farnesyl transferase inhibitors as anticancer agents mayo.
Farnesyldiphosphate farnesyltransferase wikimili, the free. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular. Effect of a farnesyl transferase inhibitor r115777 on ductal carcinoma in situ of the breast in a human xenograft model and on breast and ovarian cancer cell growth in vitro and in vivo. Cocrystal structure of protein farnesyltransferase complexed with a. The exact mechanism of action of this class of agents is, however, currently unknown. N2 protein farnesylation catalysed by the enzyme farnesyl protein transferase involves the addition of a 15carbon farnesyl group to conserved amino acid residues at the carboxyl terminus of certain proteins. View enhanced pdf access article on wiley online library html view. Us20080255191a1 benzylimidazolyl substituted 2quinoline. Farnesyl transferase inhibitors figure 1 central role for ras in the growth factormediated signal transduction cascade.
The present studies confirm that gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase i with pronounced antitumor activity and favorable toxicity profile against breast cancer in vitro and in vivo. Fdft1 encodes squalene synthase, a key regulator of cholesterol biosynthesis that catalyzes the production of squalene from farnesyl pyrophosphate and is the. Sch66336 lonafarnib is a farnesyl transferase inhibitor fti that blocks posttranslational processing of farnesylated proteins including hras. A phase i safety, pharmacological and biological study of the farnesyl. Peptides derived from the carboxyl termini of human rheb and rheb2 are in vitro substrates for farnesyl transferase but not geranylgeranyl transferase1. Other genetic changes in tumors can signal through ras dependent pathways. The drugs inhibit farnesylation of a wide range of target proteins, including ras. Rheb prenylation in cell culture was completely inhibited by sch66336, indicating a lack. The effects of r115777, a farnesyl transferase inhibitor, were investigated in cancer cell lines expressing varying levels of growth factor receptors and with differing ras status. Protein farnesyltransferase ftase catalyzes the transfer of the. Farnesylated lamins, progeroid syndromes and farnesyl.
A farnesyl transferase inhibitor induces apoptosis of insulinoma pancreatic. Tissue culture media, gentamicin, methotrexate, and phosphatefree. Pdf farnesyl transferase inhibitor resistance probed by. A mutant form of human protein farnesyltransferase exhibits. As a target enzyme we focused on protein farnesyltransferase pftase, using. There was no relationship between gene mutation, degree of farnesyl transferase inhibition or hdj2 prenylation, and clinical response to tipifarnib. High affinity for farnesyltransferase and alternative prenylation. Phase i study of the farnesyltransferase inhibitor.
T1 farnesyl transferase inhibitors as anticancer agents. Here, we report a new strategy for anticancer therapeutic age. The year 2000 will be a significant date for the field of rasrelated therapies since numerous agents will have phase ii clinical efficacy data maturing to provide proof of principle for this cancer treatment strategy. Mar 31, 2003 we have demonstrated recently that the novel ras antagonist, farnesyl thiosalycylic acid fts inhibits the growth of melanoma cells via a combination of cytostatic and pro. Farnesyltransferase inhibitors, seminars in oncology 10. Farnesylation is a posttranslational lipid modification in which a 15carbon farnesyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins in a reaction catalyzed by protein farnesyltransferase ftase. Farnesylation of p21ras by farnesyltransferase ftase is oblig. The significant efficacy of ftis as single or combined agents in preclinical studies stands in contrast with only. The present invention is directed to compounds which inhibit farnesyl protein transferase ftase and the farnesylation of the oncogene protein ras.
To examine the effects of farnesyl transferase inhibitors sch 44342 and sch 56582 on the prenylation of endogenous ras proteins in a human tumorderived cell line, we introduced the mevalonate transporter into dld1 cells. Peptidomimetic inhibitors of fptase have been designed that selectively block farnesylation in vivo and in vitro. Fgti2734 can prevent membrane localization of kras, hence solving kras resistance problem and thwarting mutant kras patientderived pancreatic tumors. Farnesyl transferase inhibitors in myeloid malignancies farnesyl transferase inhibitors in myeloid malignancies lancet, jeffrey e. Inhibition of cell growth of human hepatoma cell line hep g2 by a farnesyl protein transferase inhibitor. Farnesyl protein transferase ftase catalyzes the transfer of a 15.
Protein farnesyl transferase target selectivity is dependent. Dld1 cells are derived from a colon carcinoma and contain one normal kras allele and one activated mutant kras allele. We have demonstrated recently that the novel ras antagonist, farnesyl thiosalycylic acid fts inhibits the growth of melanoma cells via a combination of cytostatic and pro. These data will also provide an important milestone for the cancer research community since these molecules represent a small vanguard of oncology drug discovery projects. Farnesyl transferase inhibitors in myeloid malignancies. Farnesyltransferase ft itself is a heterodimeric enzyme consisting of a 49kda subunit, which houses the catalytic site of the enzyme, and a 46kda subunit, which is responsible for binding farnesyl pyrophosphate and a protein or peptide substrate.
M305733200 october 24, 2003 the journal of biological chemistry 278, 41718 41727. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesylprotein transferase and the farnesylation of the oncogene protein ras. Farnesyl transferase inhibitors andrea d basso, paul kirschmeier. With similar results, the farnesyltransferase inhibitor fti. A phase i trial of the farnesyl protein transferase. Sep 15, 2007 farnesyl transferase inhibitor resistance probed by target mutagenesis tal raz 1 division of hematologyoncology, childrens hospital boston, and department of biological chemistry and molecular pharmacology, harvard medical school, boston, ma. Farnesylprotein transferase ft, an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. The initial lead for the discovery of lonafarnib 16, a farnesyl transferase inhibitor of mutated ras protein, was identified by bishop and his colleagues from our library of compounds, which contained a large number of loratadine analogs. Tipifarnib is a potent and specific farnesyltransferase ftase inhibitor with ic of 0. Mar 27, 2019 tau inclusions are a prominent feature of many neurodegenerative diseases and are considered to be a potential therapeutic target. Farnesyl transferase inhibition for the treatment of. The farnesyl transferase inhibitors fti were the first class of compounds to show success both in vitro, using primary cultures derived from hgps patients, and in vivo, in progeria mouse models.
In the laboratory, however, treating these engineered cells with an fti already in clinical trials in cancer patients. Farnesylated lamins, progeroid syndromes and farnesyl transferase. We report a phase i trial to assess the maximum tolerated dose, toxicities, and. New tricks for human farnesyltransferase inhibitor. Human protein farnesyltransferase ftase catalyzes the addition of a c15farnesyl lipid group to the cysteine residue located in the. Patients were enrolled from january 2000 to may 2001. Phase iiiii trial of a pretransplant farnesyl transferase. Farnesyl transferase inhibitors with high purity are used in various assays for cancer and other research areas, cited by top publications, some have entered clinical trials. Expression of the farnesyl transferase gene from u. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl protein transferase and the farnesylation of the oncogene protein ras. Farnesyl transferase inhibitors, lamin maturation and hgps. Other experimental work, including mouse model studies, have examined the possibility that farnesyl transferase inhibitors can represent effective treatment for hgps. Ggti297 is a potent, cellpermeable, and selective peptidomimetic inhibitor of ggtase i compared to farnesyl transferase ftase.
Ftis have been shown to be potent inhibitors of tumor cell growth in cell culture. Farnesyl transferase inhibitors in hutchinsongilford. Farnesyl transferase inhibitor resistance probed by target mutagenesis tal raz 1 division of hematologyoncology, childrens hospital boston, and department of biological chemistry and molecular pharmacology, harvard medical school, boston, ma. This article presents an overview of preclinical studies and clinical trials of a number of independently derived farnesyltransferase inhibitors ftis. Oct 11, 2012 by johns hopkins medicine, rxpg the new hopkins research, and similar results from other labs, shows that a class of drugs known as farnesyl transferase inhibitors, or ftis, can reverse an abnormality in laboratorygrown cells engineered to mimic cells from progeria patients. To establish the maximum tolerated dose of the farnesyltransferase inhibitor lonafarnib sarasar, scheringplough corp. Protein farnesyl transferase ftase catalyzes transfer of a 15 carbon farnesyl lipid to cysteine in the cterminal ca1a2x sequence of numerous proteins including ras.
Recent work has shed light on the roles of the lamin proteins and the enzymes involved in their farnesylationdependent maturation. The specific aims of this research are to determine the effects of matingteliospore germination inhibitors on farnesyl transferase extracted from u. In normal cells ras signalling is tightly regulated, and in the. Phase ii study of the farnesyl transferase inhibitor. Farnesyltransferase an overview sciencedirect topics. The raw score gets converted to a zscore, free of setsizebias, using the mean. Phase iii doubleblind placebocontrolled study of farnesyl. Farnesyl transferase inhibitors ftis represent a new class of signaling inhibitors that is emerging in. Biheteroaryl inhibitors of farnesylprotein transferase. A protein farnesyl transferase involved in abscisic acid signal transduction in arabidopsis article pdf available in science 2735279. Considerable effort has focused on the development of selective protein farnesyl transferase ftase and protein geranylgeranyl transferase ggtase inhibitors as cancer chemotherapeutics. While considerable progress has been made in understanding how ftase. Clinical trial of a farnesyltransferase inhibitor in.
Pmc free article nagase t, kawata s, tamura s, matsuda y, inui y, yamasaki e, ishiguro h, ito t, matsuzawa y. Farnesyltransferase posttranslationallymodifies proteins by adding an isoprenoid lipid called a farnesyl group to the sh of the cysteine near the end of target proteins to form a thioether linkage. The protein prenyltransferases, protein farnesyltransferase ftase and protein geranylgeranyltransferasei ggtasei, catalyze the attachment of a 15carbon farnesyl or 20carbon geranylgeranyl moiety, respectively, to a cysteine near the cterminus of a substrate protein. Activation of this pathway by inhibiting the enzyme farnesyltransferase blocks the attachment of a neuronal protein, rhes, to the cell membrane. Farnesyl transferase inhibitor resistance probed by target. A phase i trial of the farnesyl protein transferase inhibitor. Previous studies show that ftis arrest cancer cells in mitosis. Fungal diseases of plants continue to cause yield losses, while pathogens routinely develop resistance to currently used fungicides. Farnesyl transferase inhibitors ftis are the best studied drugs and two orally bioavailable ftis tipifarnib and lonafarnib are being tested in the combination with cytotoxic drugs in phase 3 clinical trials in lung cancer. A farnesyltransferase inhibitor activates lysosomes and.
Farnesyl pyrophosphate an overview sciencedirect topics. Ras mutations are a common genetic event in human cancers. With this aim, a number of agents, designated farnesyl transferase inhibitors ftis, have been developed that possess antineoplastic activity. K and nras are geranylgeranylated in cells treated with. An important class of cellular proteins, which includes members of the p21ras family, undergoes posttranslational farnesylation, a modification required for their partition to membranes. Ras biochemistry and farnesyl transferase inhibitors. Farnesyl transferase as a target for smut and bunt disease. Tau inclusions are a prominent feature of many neurodegenerative diseases and are considered to be a potential therapeutic target. Farnesyl pyrophosphate most likely is the initial c 15 product formed by blister beetles from the prenylation sequence, based on analogy with all other organisms in which prenylation has been studied. Pdf farnesyl transferase inhibitors as potential anticancer agents.
Thus, inhibition of farnesylation is a rational strategy for suppressing the downstream function of ras proteins. Clinical trial of a farnesyltransferase inhibitor in children with hutchinsongilford progeria syndrome. We found that rheb and rheb2 mrna were elevated in various tumor cell lines relative to normal cells. Patients and methods three hundred sixtyeight patients were randomly assigned to r115777 300 mg twice daily orally for 21 days every 28 days or placebo in a 2. Farnesyltransferase ftase adds a 15carbon isoprenoid called a farnesyl group to proteins bearing a caax motif. Farnesyl diphosphate an overview sciencedirect topics. Phase ii study of the farnesyl transferase inhibitor r115777. Farnesyl transferase expression determines clinical response. Fgti2734 is a ras cterminal mimetic dual farnesyl transferase ft and geranylgeranyl transferase 1 ggt1 inhibitor with ic 50 s of 250 nm and 520 nm for ft and ggt1, respectively. A phase i trial of the farnesyl transferase inhibitor sch66336.
This phase i study was undertaken to define the toxicity, pharmacodynamics, and maximum tolerated dose of the combination of r115777, a farnesyl transferase inhibitor, with gemcitabine and cisplatin in patients with advanced solid tumors. The present invention is directed to substituted benozdiazepine compounds which inhibit farnesyl protein transferase ftase and the farnesylation of the oncogene protein ras. Farnesyl transferase expression determines clinical. Pdf clinical trial of a farnesyltransferase inhibitor in. Evidence for biological and clinical activity article pdf available in cancer research 607. Pdf farnesyl transferase inhibitors ftis have so far proved to have limited value as single agents in clinical trials. Lonafarnib is an orally bioavailable farnesyl protein transferase fptase inhibitor for hras, kras and nras with ic of 1.
A phase i trial of the farnesyl transferase inhibitor. Farnesyl transferase inhibitor sch66336 is cytostatic, pro. Farnesyl transferase inhibitorsa novel therapy for breast. Us 5852010 a inhibitors of farnesylprotein transferase. Sqs participates in the isoprenoid biosynthetic pathway, catalyzing a twostep reaction in which two identical molecules of farnesyl pyrophosphate fpp are converted into squalene, with the consumption of nadph. Efficacy of sch66336, a farnesyl transferase inhibitor, in.
This process, called farnesylation which is a type of prenylation, causes farnesylated proteins to become membraneassociated due to the hydrophobic nature of the farnesyl group. Rhes is farnesylated and treatment with the farnesyl transferase inhibitor, lonafarnib, reduced rhes, attenuated behavioral abnormalities, significantly reduced atrophy, tau inclusions, sumoylation and ubiquitination, as well as microgliosis in the rtg4510 tauopathy mouse. Interestingly, the mtor inhibitor rapamycin also blocked the serumfree growth of these cells but did not result in normalization of the actin. Evidence for biological and clinical activity, abstract farnesyl protein transferase ft, an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of. Farnesyl transferase inhibitors can be effective as anti. Farnesyltransferase and geranylgeranyltransferasei fierke. We conducted an in vitro screen for resistance to lonafarnib, a farnesyl protein transferase inhibitor that blocks prenylation of a number of proteins important in cell proliferation, and. Farnesylation is the first and most critical step in the posttranslation modification of ras proteins 10. Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. Farnesyl transferase is necessary for this movement to take place. Effects on tumour xenografts and human ductal carcinoma in situ dcis of the breast in a xenograft mouse model were also tested.
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