Target Validation Information
Target ID T64081
Target Name Farnesyltransferase
Target Type
Discontinued
Drug Potency against Target AZD3409 Drug Info IC50 = 3~14.2 nM [553030]
L-778123 Drug Info IC50 = 98 nM [526941]
CLAVARINONE Drug Info IC50 = 8000 nM [534739]
MANUMYCIN A Drug Info IC50 = 11900 nM [526603]
Zarnestra Drug Info IC50 = 0.86 nM [552675]
Lonafarnib Drug Info IC50 = 1.9 nM [552350]
L-745631 Drug Info IC50 = 10000 nM [534466]
ACTINOPLANIC ACID A Drug Info IC50 = 230 nM [534466]
RPR-113829 Drug Info IC50 = 17.5 nM [534405]
Pseudopeptide derivative Drug Info IC50 = 50 nM
PB-27 Drug Info IC50 = 2.8 nM [527568]
RPR-114334 Drug Info IC50 = 500 nM [534405]
BMS-404683 Drug Info IC50 = 1.4 nM [527568]
PD-83176 Drug Info IC50 = 10 nM [534307]
(Z)-2-Methyl-3-tetradecyl-but-2-enedioic acid Drug Info IC50 = 60 nM [534466]
BMS214662 Drug Info Ki = 0.93 nM [552675]
SCH-44342 Drug Info IC50 = 250 nM [525518]
L-731735 Drug Info IC50 = 20 nM [534664]
ABT-839 Drug Info IC50 = 1.1 nM [526584]
PB-81 Drug Info IC50 = 1000 nM [527568]
PB-80 Drug Info IC50 = 25 nM [527568]
Action against Disease Model Zarnestra R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 h uMan t uMor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777. The majority of sensitive cell lines had a wild-type ras gene. T uMor cell lines bearing H-ras or N-ras mutations were among the most sensitive of the cell lines tested, with responses observed at nanomolar concentrations of R115777. T uMor cell lines bearing mutant K-ras genes required higher concentrations for inhibition of cell growth, with 50% of the cell lines resistant to R115777 up to concentrations of 500 nM. Inhibition of H-Ras, N-Ras, and lamin B protein processing was observed at concentrations of R115777 that inhibited cell proliferation [552244] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations We designed a specific siRNA directed against the beta subunit of the alpha/beta FTase heterodimer and shown that the siRNA represses expression of the FTase beta gene and inhibits the enzymatic activity of FTase but not of the closely related family member geranylgeranyltransferase I. Prenylation of target substrates such as Ras was also decreased by FT? specific siRNA. FT?knockdown resulted in morphological reversion of H-Ras transforrmed cells and decreased cell viability. In addition, FT? siRNA, but not control siRNAs, decreased cell proliferation and increased celldeath. FT? specific siRNA reduced MAPK but not Akt activation. Finally, we observed that t uMor growth in a mouse xenograft model of h uMan lung A-549 t uMors was impaired by in vivo injection of siRNA specific to FT?, but not control siRNA. Our findings show that inhibition of FTase expression in h uMan cancer cells impairs t uMor growth in vivo. [553030]
References
Ref 553030Characterization of the in vitro activity of AZD3409, a novel prenyl transferase inhibitor. Cancer Chemother Pharmacol. 2011 Jan;67(1):137-45. doi: 10.1007/s00280-010-1300-6. Epub 2010 Mar 13.
Ref 552244Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res. 2001 Jan 1;61(1):131-7.
Ref 526941Bioorg Med Chem Lett. 2004 Feb 9;14(3):639-43.Macrocyclic piperazinones as potent dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I.
Ref 534739J Med Chem. 1998 Nov 5;41(23):4492-501.Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase.
Ref 526603Bioorg Med Chem Lett. 2003 May 5;13(9):1523-6.A novel metal-chelating inhibitor of protein farnesyltransferase.
Ref 552675Targeting the RAS signaling pathway in malignant hematologic diseases. Curr Drug Targets. 2007 Feb;8(2):217-35.
Ref 552350Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations. Curr Top Med Chem. 2003;3(10):1103-14.
Ref 534466J Med Chem. 1997 Sep 12;40(19):2971-90.Ras farnesyltransferase: a new therapeutic target.
Ref 534466J Med Chem. 1997 Sep 12;40(19):2971-90.Ras farnesyltransferase: a new therapeutic target.
Ref 534405J Med Chem. 1997 Jun 6;40(12):1763-7.Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase.
Ref 527568J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.
Ref 534405J Med Chem. 1997 Jun 6;40(12):1763-7.Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase.
Ref 527568J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.
Ref 534307J Med Chem. 1997 Jan 17;40(2):192-200.Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase.
Ref 534466J Med Chem. 1997 Sep 12;40(19):2971-90.Ras farnesyltransferase: a new therapeutic target.
Ref 552675Targeting the RAS signaling pathway in malignant hematologic diseases. Curr Drug Targets. 2007 Feb;8(2):217-35.
Ref 525518J Med Chem. 1999 Jun 17;42(12):2125-35.Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships.
Ref 534664J Med Chem. 1998 Jul 2;41(14):2651-6.N-Arylalkyl pseudopeptide inhibitors of farnesyltransferase.
Ref 526584Bioorg Med Chem Lett. 2003 Apr 7;13(7):1359-62.Aryl tetrahydropyridine inhibitors of farnesyltransferase: glycine, phenylalanine and histidine derivatives.
Ref 527568J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.
Ref 527568J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.

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