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. Metabolism of ethanol and carcinogens by glutathione transferases. 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. 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. Three mammalian nuclear lamin proteins, lamin b1, lamin b2 and the lamin a precursor, prelamin a, undergo canonical farnesylation and processing at caax motifs. The farnesyl transferase inhibitor lonafarnib inhibits. A transferase is any one of a class of enzymes that enact the transfer of specific functional. Clinical trials using these new agents have shown great promise. 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. The drugs inhibit farnesylation of a wide range of target proteins, including ras.
The present invention is directed to compounds which inhibit farnesyl protein transferase ftase and the farnesylation of the oncogene protein ras. 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. K and nras are also substrates of farnesyl transferase. The role of glutathione transferases in the development of. With these purified preparations, free fatty acid was found to be the lipid.
Farnesyl and geranylgeranyl transferase inhibitors induce. This article presents an overview of preclinical studies and clinical trials of a number of independently derived farnesyltransferase inhibitors ftis. Similar genes were identified in other butyrateproducing human gut bacteria from. Significantly, this is dependent on the caax farnesylation motif.
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. Barceloneic acid a, a new farnesylprotein transferase. 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. Upregulation of the glutathione stransferase system in. Further, fti treatment of the mcf7 cell line leads to profound changes in rho gtpase activation 10. Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial activity. 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. Status of lipid peroxidation, glutathione, ascorbic acid, vitamin e and. Us6040305a compounds useful for inhibition of farnesyl. Farnesylated lamins, progeroid syndromes and farnesyl. Ftase, protein prenyl transferases jena bioscience. Ganguly, in annual reports in medicinal chemistry, 20.
The present invention is directed to substituted benozdiazepine compounds which inhibit farnesyl protein transferase ftase and the farnesylation of the oncogene protein ras. Phase ii study of the farnesyl transferase inhibitor. Serial measurements of farnesylated and unfarnesylated hdj2 were performed to indicate depth of farnesyl transferase. 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. 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. Open access effect of a farnesyl transferase inhibitor. It was not totally surprising that one of them showed activity. Preclinical and clinical pharmacodynamic assessment of l. Mutant kras is a major driver of pancreatic oncogenesis and therapy resistance, yet kras inhibitors are lacking in the clinic. Lonafarnib sch66336 is a farnesyl transferase inhibitor fti that inhibits the posttranslational lipid modification of hras and other farnesylated proteins. Hutchinsongilford progeria hgps and restrictive dermopathy rd. Cytoreductive effects of farnesyl transferase inhibitors. 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.
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. The isoprenoids farnesylfpp and geranylgeranylpyrophosphate fpp and ggpp are two major lipid intermediates in the mevalonate pathway. Breastcancerstemcellssurviveperiodsoffarnesyltransferase. 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. Read corrigendum to preclinical metabolism of lb42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome p450 isozyme activities bioorg. L778,123, an inhibitor of fptase and ggptasei, was developed in part because it can completely inhibit kiras prenylation. 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. Mutations in the ras family of oncogenes are common in human cancers 4, and have been associated with. The key step involves a stereoselective addition of the heterocyclic zinc reagent 10 to chiral. Farnesyl transferase inhibition for the treatment of tauopathies. A new paradigm for cancer chemotherapy, advances in discovery and development of natural product inhibitors. However, kras becomes geranylgeranylated and active when cancer cells are treated with ftis.
Dual farnesyl and geranylgeranyl transferase inhibitor. 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. A rapid and sensitive assay for determining human brain. 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. Because oncogenic ras mutations are found in up to 50% of multiple myeloma mm specimens, these agents may be effective in this disease. A novel class of coatransferase involved in short chain fatty acid. Farnesyl transferase is a heterodimer transferase that targets ras proteins and attaches a farnesyl group to it. Two prenyl transferase encoding genes, fps and crte, were expressed in e. This addition is necessary for the biological function of the modified proteins. Borthakur g1, kantarjian h, daley g, talpaz m, obrien s, garciamanero g, giles f, faderl s, sugrue m, cortes j. Effect of a farnesyl transferase inhibitor r115777 on. Farnesyl transferase inhibition for the treatment of. In the case of prelamin a, there is an additional farnesylationdependent endoproteolysis, which is defective in two congenital diseases. Ep0535731a2 inhibitors of farnesyl protein transferase.
By inhibition of ras farnesylation, a blockade of the signal transduction pathway is accomplished with cessation of cell growth. 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. Ggti297 is a potent, cellpermeable, and selective peptidomimetic inhibitor of ggtase i compared to farnesyl transferase ftase. Farnesyl transferase and geranylgeranyl transferase catalyze the attachment of a farnesyl or geranylgeranyl isoprenoid to a.
Corrigendum to preclinical metabolism of lb42908, a novel. Farnesyl trans transferase an overview sciencedirect. A promising way of interfering with ras function seemed to be the inhibition of farnesyl transferase, the enzyme coupling a 15. 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. Farnesyl transferase inhibitors cause enhanced mitotic. Specifically, rhoa gtpase becomes hypoactivated while rhoc gtpasebecomes hyperactivated. Potential targets and biological modes of action of ftis are discussed, and the results of clinical trials are summarized. 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. We discovered a novel regulatory pathway for tau degradation that operates through the rhes. Glutathione stransferases of the bovine retina ncbi. The exact mechanism of action of this class of agents is, however, currently unknown. Also disclosed are methods of inhibiting farnesyl protein transferase and the growth of abnormal cells, such as tumor cells.
Kras requires farnesylation for membrane localization and cancercausing activity prompting the development of farnesyltransferase inhibitors ftis as anticancer agents. 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. However, some preclinical studies suggest that fti antitumor responses are unrelated to effects on ras. 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. Crystallization of the product as the dimeric zinc complex facilitates isolation of product in 99.
To support the clinical development of l778,123, we. Farnesyl and geranylgeranyl transferase inhibitors induce g 1 arrest by targeting the proteasome ekem t. This ras protein, on localization to the cell membrane, has the ability to induce. Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. The ras pathway is essential for cell growth and proliferation. The crystallographic structure of acetylcysvalileselenometcooh and alphahydroxyfarnesylphosphonic acid alphahfp complexed with rat farnesyl protein transferase fpt space group p61, a b 174.
The combination of the farnesyl transferase inhibitor. Efuet and khandan keyomarsi cancer res january 15 2006 66 2 10401051. 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. Specific farnesyl transferase inhibitors ftis have been developed that selectively inhibit the processing of these proteins. Us 5852010 a inhibitors of farnesylprotein transferase. Gliotoxin is a dual inhibitor of farnesyltransferase and.
Here, we show that ectopic expression of the kinetochore targeting domain of cenpf delays progression through g2m. Recently, the kinetochore protein cenpf has been shown to be farnesylated. Tau inclusions are a shared feature of many neurodegenerative conditions and tau mutations lead to frontotemporal dementia. A stereoselective synthesis of abt100 1, a novel farnesyl transferase inhibitor, is described. A phase i trial of the farnesyl protein transferase. Farnesyl transferase inhibitors ftis have so far proved to have limited value as single agents in clinical trials. Several different farnesyl transferase inhibitors ftis have been developed. Ras, rhob, pxf, rap2, and cyclic gmp phosphodiesterase. Biheteroaryl inhibitors of farnesylprotein transferase. An important class of cellular proteins, which includes members of the p21ras family, undergoes posttranslational farnesylation, a modification required for their partition to membranes. We recently showed that these novel ftis in combination. Rhes is farnesylated and treatment with the farnesyl transferase inhibitor, lonafarnib, reduced rhes. Glutathione transferases are multifunctional enzymes. 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 diphosphate and geranylgeranyldiphosphate are respectively involved in farnesylation and geranylgeranylation of a variety of proteins. This multicenter phase ii study was conducted to determine the efficacy, tolerability and pharmacokinetics of r115777 in patients with relapsed smallcell lung cancer sclc. Effects on tumour xenografts and human ductal carcinoma in situ dcis of the breast in a xenograft mouse model were also tested. The significant efficacy of ftis as single or combined agents in preclinical studies stands in contrast with only. Fti277 trifluoroacetate salt is an inhibitor of farnesyl transferase that displays antagonistic activity towards both h and kras oncogenic signaling. Thus the coatransferase preferentially uses butyrylcoa as substrate. Farnesylation of cenpf is required for g2m progression. Farnesyl transferase inhibitor resistance probed by target. 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. 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. We have purified two isoenzymes of glutathione stransferase from bovine retina to.
Due to the important role of these proteins in a number of cell. The cytosolic glutathione stransferases comprise a pivotal enzyme system protecting the cell from. Ftis have been shown to be potent inhibitors of tumor cell growth in cell culture. They participate in posttranslational modification of members of the superfamily of small guanosine triphosphatases gtpases. Farnesyl transferase expression determines clinical. Farnesyl transferase inhibitors ftis are anticancer agents designed to target ras processing and rasdependent signal pathways. Terminal transferase tdt is a polymerase that catalyzes the addition of deoxynucleotides to the 3 hydroxyl terminus of dna molecules. Searching for the elusive targets of farnesyltransferase. Farnesyl transferase activity was measured with a scintillation proximity assay amersham biosciences, piscataway, nj as previously described 21, 28.
245 1246 332 701 1093 562 976 1356 232 1256 520 490 386 229 680 836 238 310 848 1188 716 566 1455 1051 787 206 1183 456 1059 679 553 924 561 308 357 1378 301 161 1334 841 693 165