Aspartate carbamyl transferase from escherichia coli pdf. Farnesyl transferase inhibition for the treatment of. Farnesyl protein transferase ftase catalyzes the transfer of a farnesyl group from farnesyl diphosphate fpp to a specific cysteine residue of a substrate protein through covalent attachment1,2. In the case of prelamin a, there is an additional farnesylationdependent endoproteolysis, which is defective in two congenital diseases. The ras pathway is essential for cell growth and proliferation. However, some preclinical studies suggest that fti antitumor responses are unrelated to effects on ras. Farnesyl transferase inhibition for the treatment of tauopathies.
Effect of a farnesyl transferase inhibitor r115777 on. Farnesyl transferase expression determines clinical. It was not totally surprising that one of them showed activity. Breastcancerstemcellssurviveperiodsoffarnesyltransferase. A rapid and sensitive assay for determining human brain. Farnesyl transferase and geranylgeranyl transferase catalyze the attachment of a farnesyl or geranylgeranyl isoprenoid to a. Farnesyl transferase activity was measured with a scintillation proximity assay amersham biosciences, piscataway, nj as previously described 21, 28. Farnesylation of cenpf is required for g2m progression. An important class of cellular proteins, which includes members of the p21ras family, undergoes posttranslational farnesylation, a modification required for their partition to membranes. Specific farnesyl transferase inhibitors ftis have been developed that selectively inhibit the processing of these proteins.
A report from the childrens oncology group elliot stieglitz md department of pediatrics, helen diller comprehensive cancer center, university of california san francisco school of medicine and benioff childrens hospital, san francisco. Farnesyl transferase inhibitors ftis have so far proved to have limited value as single agents in clinical trials. This pharmsight will focus on the use of a novel group of ftis that are most effective in vitro when used in combination with the statin class of antihypercholesterolemic agents, which also block protein prenylation. K and nras are also substrates of farnesyl transferase. Significantly, this is dependent on the caax farnesylation motif. Xray diffraction studies of bms214662 and tipifarnib complexed with farnesyl transferase show that they bind to a hydrophobic cleft formed at the interface of the. Farnesyl diphosphate and geranylgeranyldiphosphate are respectively involved in farnesylation and geranylgeranylation of a variety of proteins. Several different farnesyl transferase inhibitors ftis have been developed. Farnesylation makes the ras protein more hydrophobic, and therefore it becomes possible for the protein to attach to the plasma membrane 10. Terminal transferase tdt is a polymerase that catalyzes the addition of deoxynucleotides to the 3 hydroxyl terminus of dna molecules. 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. Ftase catalyzes the transfer of the farnesyl group from farnesyl diphosphate to proteins containing a cterminal caax motif, where c is a conserved cysteine that is the site of farnesyl modification, a is usually an aliphatic amino acid, and. Mutations in the ras family of oncogenes are common in human cancers 4, and have been associated with. Us 5852010 a inhibitors of farnesylprotein transferase.
Lonafarnib sch66336 is a farnesyl transferase inhibitor fti that inhibits the posttranslational lipid modification of hras and other farnesylated proteins. Also disclosed are methods of inhibiting farnesyl protein transferase and the growth of abnormal cells, such as tumor cells. Ftis have been shown to be potent inhibitors of tumor cell growth in cell culture. The farnesyl transferase inhibitor lonafarnib inhibits. A transferase is any one of a class of enzymes that enact the transfer of specific functional.
Due to the important role of these proteins in a number of cell. Gliotoxin is a dual inhibitor of farnesyltransferase and. The drugs inhibit farnesylation of a wide range of target proteins, including ras. 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. The role of glutathione transferases in the development of. 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. Glutathione transferases are multifunctional enzymes. Farnesyl transferase is a heterodimer transferase that targets ras proteins and attaches a farnesyl group to it. Farnesylated lamins, progeroid syndromes and farnesyl. Borthakur g1, kantarjian h, daley g, talpaz m, obrien s, garciamanero g, giles f, faderl s, sugrue m, cortes j. Us6040305a compounds useful for inhibition of farnesyl. Farnesyl and geranylgeranyl transferase inhibitors induce g 1 arrest by targeting the proteasome ekem t. Farnesyl trans transferase an overview sciencedirect. 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.
Farnesyl transferase inhibitors induce g2m cell cycle delays that cannot be explained by inhibition of the ras gtpase. Thus the coatransferase preferentially uses butyrylcoa as substrate. L778,123, an inhibitor of fptase and ggptasei, was developed in part because it can completely inhibit kiras prenylation. The farnesyl transferase inhibitor lonafarnib inhibits mtor signaling and enforces sorafenibinduced apoptosis in melanoma cells heike niessner1, daniela beck1, tobias sinnberg1, konstantinos lasithiotakis1, evelyn maczey1, jeannette gogel1, sascha venturelli2, alexander berger2, mario mauthe3, mahmoud toulany4, keith flaherty5, martin schaller1, dirk schadendorf6, tassula proikas. The protein farnesyltransferase ftase catalyzes addition of the hydrophobic farnesyl isoprenoid to a cysteine residue fourth from the c terminus of several protein acceptors that are essential for cellular signal transduction such as ras and rho. Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. Aaml0122 was a childrens oncology groupsponsored clinical trial to assess the safety and efficacy of a farnesyl transferase inhibitor and chemotherapy in patients with jmml. Potential targets and biological modes of action of ftis are discussed, and the results of clinical trials are summarized. Here, we show that ectopic expression of the kinetochore targeting domain of cenpf delays progression through g2m. Glutathione stransferases of the bovine retina ncbi.
Read corrigendum to preclinical metabolism of lb42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome p450 isozyme activities bioorg. The crystallographic structure of acetylcysvalileselenometcooh and alphahydroxyfarnesylphosphonic acid alphahfp complexed with rat farnesyl protein transferase fpt space group p61, a b 174. The cytosolic glutathione stransferases comprise a pivotal enzyme system protecting the cell from. Efuet and khandan keyomarsi cancer res january 15 2006 66 2 10401051. Ggti297 is a potent, cellpermeable, and selective peptidomimetic inhibitor of ggtase i compared to farnesyl transferase ftase. The significant efficacy of ftis as single or combined agents in preclinical studies stands in contrast with only. Corrigendum to preclinical metabolism of lb42908, a novel. They participate in posttranslational modification of members of the superfamily of small guanosine triphosphatases gtpases. Kras requires farnesylation for membrane localization and cancercausing activity prompting the development of farnesyltransferase inhibitors ftis as anticancer agents. The exact mechanism of action of this class of agents is, however, currently unknown. As a part of our efforts to identify potent inhibitors of farnesyltransferase ftase, modification of the structure of tipifarnib through structurebased design was undertaken by replacing the 2quinolones with 4quinolones and pyridones, and subsequent relocation of the d.
By inhibition of ras farnesylation, a blockade of the signal transduction pathway is accomplished with cessation of cell growth. Farnesyl transferase inhibitors ftis are anticancer agents designed to target ras processing and rasdependent signal pathways. Open access effect of a farnesyl transferase inhibitor. Status of lipid peroxidation, glutathione, ascorbic acid, vitamin e and. A promising way of interfering with ras function seemed to be the inhibition of farnesyl transferase, the enzyme coupling a 15. We recently showed that these novel ftis in combination. Clinical trials using these new agents have shown great promise. A stereoselective synthesis of abt100 1, a novel farnesyl transferase inhibitor, is described.
Further, fti treatment of the mcf7 cell line leads to profound changes in rho gtpase activation 10. Crystallization of the product as the dimeric zinc complex facilitates isolation of product in 99. Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy. Mutant kras is a major driver of pancreatic oncogenesis and therapy resistance, yet kras inhibitors are lacking in the clinic. This multicenter phase ii study was conducted to determine the efficacy, tolerability and pharmacokinetics of r115777 in patients with relapsed smallcell lung cancer sclc. The combination of the farnesyl transferase inhibitor. A new paradigm for cancer chemotherapy, advances in discovery and development of natural product inhibitors. The farnesyl transferase inhibitors ftis have historically been agents directed at the rasrafmitogenactivated protein kinase mapk pathway, 9,10 however, emerging data suggests that among patients with responses to the ftis, these occur independent of ras mutations. However, kras becomes geranylgeranylated and active when cancer cells are treated with ftis. To support the clinical development of l778,123, we. Searching for the elusive targets of farnesyltransferase. Two prenyl transferase encoding genes, fps and crte, were expressed in e.
Cytoreductive effects of farnesyl transferase inhibitors. Rhes is farnesylated and treatment with the farnesyl transferase inhibitor, lonafarnib, reduced rhes. The isoprenoids farnesylfpp and geranylgeranylpyrophosphate fpp and ggpp are two major lipid intermediates in the mevalonate pathway. The key step involves a stereoselective addition of the heterocyclic zinc reagent 10 to chiral. This ras protein, on localization to the cell membrane, has the ability to induce. 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.
Biheteroaryl inhibitors of farnesylprotein transferase. Specifically, rhoa gtpase becomes hypoactivated while rhoc gtpasebecomes hyperactivated. Barceloneic acid a, a new farnesylprotein transferase. Farnesyltransferase ftase inhibitors ftis were developed originally as antiras compounds and novel targetbased drugs for cancer treatment. Pdf farnesyl transferase inhibition for the treatment of. Farnesyl and geranylgeranyl transferase inhibitors induce.
Ganguly, in annual reports in medicinal chemistry, 20. We have purified two isoenzymes of glutathione stransferase from bovine retina to. Metabolism of ethanol and carcinogens by glutathione transferases. Preclinical and clinical pharmacodynamic assessment of l. A phase i trial of the farnesyl protein transferase.
With these purified preparations, free fatty acid was found to be the lipid. Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial activity. This article presents an overview of preclinical studies and clinical trials of a number of independently derived farnesyltransferase inhibitors ftis. This addition is necessary for the biological function of the modified proteins. Farnesylation and geranylgeranylation are required for the ability of ras and rho proteins to induce malignant transformation, invasion, and metastasis. This posttranslational modification is involved in membrane association due to the enhanced hydrophobicity of protein.
Hutchinsongilford progeria hgps and restrictive dermopathy rd. Three mammalian nuclear lamin proteins, lamin b1, lamin b2 and the lamin a precursor, prelamin a, undergo canonical farnesylation and processing at caax motifs. Phase ii study of the farnesyl transferase inhibitor. We discovered a novel regulatory pathway for tau degradation that operates through the rhes.
Ftase, protein prenyl transferases jena bioscience. R115777 tipifarnib, zarnestra is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. A novel class of coatransferase involved in short chain fatty acid. Because oncogenic ras mutations are found in up to 50% of multiple myeloma mm specimens, these agents may be effective in this disease. Upregulation of the glutathione stransferase system in. Approaches to treatment of these conditions have focused directly on the tau protein by targeting its posttranslational modifications, its levels and its tendency to aggregate. Dual farnesyl and geranylgeranyl transferase inhibitor. The present invention is directed to substituted benozdiazepine compounds which inhibit farnesyl protein transferase ftase and the farnesylation of the oncogene protein ras. Recently, the kinetochore protein cenpf has been shown to be farnesylated. 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.
Serial measurements of farnesylated and unfarnesylated hdj2 were performed to indicate depth of farnesyl transferase. Functional characterization of the xanthophyllomyces. Fti277 trifluoroacetate salt is an inhibitor of farnesyl transferase that displays antagonistic activity towards both h and kras oncogenic signaling. 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. 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. Ep0535731a2 inhibitors of farnesyl protein transferase. Similar genes were identified in other butyrateproducing human gut bacteria from. The present invention is directed to compounds which inhibit farnesyl protein transferase ftase and the farnesylation of the oncogene protein ras. Ras, rhob, pxf, rap2, and cyclic gmp phosphodiesterase. Farnesyl transferase inhibitors cause enhanced mitotic. Tau inclusions are a shared feature of many neurodegenerative conditions and tau mutations lead to frontotemporal dementia. Farnesyl transferase inhibitor resistance probed by target. Effects on tumour xenografts and human ductal carcinoma in situ dcis of the breast in a xenograft mouse model were also tested. 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.
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