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