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