Disease relevance of FNTAL1

• Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma [1].
• Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting [2].
• PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs) [3].
• Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype [4].
• Thus, in the current study, we investigated whether BMS-186511, a bisubstrate analogue inhibitor of FT, would inhibit the malignant growth properties of a cell line established from malignant schwannoma of an NF1 patient [4].

High impact information on FNTAL1

• Protein farnesyltransferase is a heterodimeric enzyme that attaches a farnesyl group to cysteine in ras proteins and other membrane-associated proteins [5].
• Transfection of the beta subunit cDNA produced farnesyltransferase activity in human kidney cells, but only when it was transfected together with a cDNA encoding part of the alpha subunit [5].
• Protein farnesyltransferase (FTase) catalyses the attachment of a farnesyl lipid group to numerous essential signal transduction proteins, including members of the Ras superfamily [6].
• Replacement of the two aliphatic residues with a benzodiazepine-based mimic of a peptide turn generated potent inhibitors of farnesyltransferase [50 percent inhibitory concentration (IC50) < 1 nM] [7].
• The farnesyltransferase that catalyzes this reaction recognizes tetrapeptides of the sequence CAAX, where C is cysteine, A is an aliphatic amino acid, and X is a carboxyl-terminal methionine or serine [7].

Chemical compound and disease context of FNTAL1

• PURPOSE: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models [8].
• The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples [9].
• Here we show that FTI-277, another farnesyltransferase inhibitor, prevented the production of complete, infectious HDV virions of two different genotypes [10].
• Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent [11].
• Inhibition of growth and invasive activity of human pancreatic cancer cells by a farnesyltransferase inhibitor, manumycin [12].

Biological context of FNTAL1

• Although previous studies have shown that FT inhibitors can block the growth of tumor cells carrying mutant Ras proteins, it remained unclear how this class of inhibitors would affect tumor cells such as in NF1, whose malignant growth appears to be mediated by up-regulation of wild-type Ras activity [4].
• Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen [8].
• Ras oncogene encode a protein p2l which in its mutated form transforms mammalian cells only after membrane anchoring by a series of enzymatic reactions where the initial step is catalyzed by farnesyltransferase (FTase) [13].
• Farnesyltransferase as a target for anticancer drug design [14].
• Recent work suggests that farnesyltransferase inhibitors suppress cancer cell proliferation through mechanisms other than inhibiting Ras isoprenylation, which is not a crucial event [15].

Anatomical context of FNTAL1

• Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells [1].
• FT-mediated post-translational farnesylation of Ras proteins is absolutely necessary for Ras function since this modification is required for the anchoring of Ras proteins to the plasma cell membrane [4].
• This last group of compounds has been most successful in showing highly potent inhibition of FTase and selective blocking of Ras processing in a range of Ras transformed tumor cell lines at concentrations as low as 10 nM [14].
• Overall, these studies provide a new insight into the functional relationship between HDAC6, farnesyltransferase, and microtubules, and support clinical data showing that the FTI/taxane combination is effective in taxane-refractory patients [16].
• Both compounds were equally effective in inhibiting Ras processing and causing accumulation of a variety of nonfarnesylated substrates of FT in HCT-116 cells [17].

Associations of FNTAL1 with chemical compounds

• We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS [2].
• Therefore, the mechanisms and effects of combined therapy of statins or farnesyltransferase inhibitors with chemotherapeutics, biphosphonates, non-steroidal anti-inflammatory drugs, specific inhibitors of geranylgeranyltransferase and inhibitors of tyrosine kinase activity are discussed [18].
• Farnesyltransferase catalyses the post-translational modification of proteins by a cholesterol precursor, farnesylpyrophosphate [19].
• Protein farnesyltransferase (FTase) catalyzes the attachment of a farnesyl lipid group to the cysteine residue located in the C-terminal tetrapeptide of many essential signal transduction proteins, including members of the Ras superfamily [20].
• Here, we present the crystal structure of human FTase, as well as ternary complexes with the TKCVFM hexapeptide substrate, CVFM non-substrate tetrapeptide, and L-739,750 peptidomimetic with either farnesyl diphosphate (FPP), or a nonreactive analogue [20].

Analytical, diagnostic and therapeutic context of FNTAL1

• FTase inhibitors are currently in clinical trials for the treatment of cancer [6].
• Farnesyltransferase inhibitors could therefore be of use as sensitizers for pancreatic carcinoma radiotherapy [21].
• FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15 [22].
• Molecular cloning and characterization of a protein farnesyltransferase from the enteric protozoan parasite Entamoeba histolytica [23].
• EXPERIMENTAL DESIGN: In the present study, we investigated the effects of a novel farnesyltransferase inhibitor, ABT-100, on human liver cancer cell lines, HepG2 and Huh7, and on an animal model of hepatocarcinogenesis [11].

References