Disease relevance of FNTAL2

• CONCLUSION: Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC [1].
• A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation [2].
• In vitro and in vivo evaluation of two rational-designed nonpeptidic farnesyltransferase inhibitors on HT29 human colon cancer cell lines [3].
• Farnesyltransferase inhibitors and rapamycin in the treatment of multiple myeloma [4].
• PURPOSE: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs) [5].

High impact information on FNTAL2

• These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LADelta50 [6].
• 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 [7].
• The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors [8].
• Furthermore, a farnesyltransferase inhibitor interacted synergistically with the Eg5 inhibitor in inducing apoptosis through disrupting the Akt/Hsp70 signaling axis [9].
• PURPOSE: To establish the maximum tolerated dose of the farnesyltransferase inhibitor lonafarnib (Sarasar, Schering-Plough Corp., Kenilworth, NJ) in combination with weekly paclitaxel in patients with solid tumors [10].

Chemical compound and disease context of FNTAL2

• Targeted inhibition of farnesyltransferase in locally advanced breast cancer: a phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide [1].

Biological context of FNTAL2

• One such modification, the covalent attachment of a single isoprenoid lipid (prenylation), is carried out by the CaaX prenyltransferases, protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type-I (GGTase-I) [11].
• A single binding site model that was derived from the crystal structure of CVFM complexed with farnesyltransferase and farnesylpyrophosphate was used for these studies [12].
• In parallel, farnesyltransferase and MEK inhibitors blocked ERK phosphorylation and neuroprotective effect of NAC [13].
• Exploring structure-activity relationships of tricyclic farnesyltransferase inhibitors using ECLiPS libraries [14].
• Summarized, these observations indicate that the CAAX box-mediated processing steps of Pex19p are dispensable for peroxisome biogenesis in yeast and mammalian cells [15].

Anatomical context of FNTAL2

• The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line [14].
• Therefore, pharmacological inhibitors of FTase (FTIs) and GGTase I (GGTIs) have been developed to prevent these modifications and thereby to block the lipid-mediated association of Ras and Rho proteins with cellular membranes and the consequent signaling and transforming activities [16].
• The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells [17].
• Our previous studies demonstrated that manumycin A, a farnesyltransferase inhibitor, induced apoptosis of anaplastic thyroid cancer cells via the intrinsic apoptosis pathway and induced reactive oxygen species (ROS), which mediated DNA damage [18].

Associations of FNTAL2 with chemical compounds

• Although FTase and GGTase-I are highly homologous, they are quite selective for their substrates, particularly for their isoprenoid diphosphate substrates, FPP and GGPP, respectively [11].
• The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib [1].
• Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential [19].
• Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described [19].
• The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM) [19].

References