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 553030 | Characterization 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 552244 | Characterization 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 526941 | Bioorg Med Chem Lett. 2004 Feb 9;14(3):639-43.Macrocyclic piperazinones as potent dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I. | ||||
Ref 534739 | J 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 526603 | Bioorg Med Chem Lett. 2003 May 5;13(9):1523-6.A novel metal-chelating inhibitor of protein farnesyltransferase. | ||||
Ref 552675 | Targeting the RAS signaling pathway in malignant hematologic diseases. Curr Drug Targets. 2007 Feb;8(2):217-35. | ||||
Ref 552350 | Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations. Curr Top Med Chem. 2003;3(10):1103-14. | ||||
Ref 534466 | J Med Chem. 1997 Sep 12;40(19):2971-90.Ras farnesyltransferase: a new therapeutic target. | ||||
Ref 534466 | J Med Chem. 1997 Sep 12;40(19):2971-90.Ras farnesyltransferase: a new therapeutic target. | ||||
Ref 534405 | J Med Chem. 1997 Jun 6;40(12):1763-7.Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase. | ||||
Ref 527568 | J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. | ||||
Ref 534405 | J Med Chem. 1997 Jun 6;40(12):1763-7.Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase. | ||||
Ref 527568 | J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. | ||||
Ref 534307 | J Med Chem. 1997 Jan 17;40(2):192-200.Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. | ||||
Ref 534466 | J Med Chem. 1997 Sep 12;40(19):2971-90.Ras farnesyltransferase: a new therapeutic target. | ||||
Ref 552675 | Targeting the RAS signaling pathway in malignant hematologic diseases. Curr Drug Targets. 2007 Feb;8(2):217-35. | ||||
Ref 525518 | J Med Chem. 1999 Jun 17;42(12):2125-35.Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships. | ||||
Ref 534664 | J Med Chem. 1998 Jul 2;41(14):2651-6.N-Arylalkyl pseudopeptide inhibitors of farnesyltransferase. | ||||
Ref 526584 | Bioorg Med Chem Lett. 2003 Apr 7;13(7):1359-62.Aryl tetrahydropyridine inhibitors of farnesyltransferase: glycine, phenylalanine and histidine derivatives. | ||||
Ref 527568 | J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. | ||||
Ref 527568 | J Med Chem. 2005 Jun 2;48(11):3704-13.Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. |
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