Structures of Protein Farnesyltransferase

Long, Stephen B.; Beese, L.S.

doi:10.1385/1-59259-013-6:37

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“…structure of the FPT enzyme had not been published nor had the active site been defined [3][4][5][6][7][8]. Little was published on FPT inhibitors aside from the original CAAX tetrapeptides and two early peptidomimetic series [9,10].…”

Section: Introductionmentioning

confidence: 99%

Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery

Venet¹,

End²,

Angibaud

2003

CTMC

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R115777 (R)-6-amino[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. Taking its roots into Janssen's ketoconazole and retinoic acid catabolism programs, our interest into Ras prenylation process led us stepwise to identify the key structural features of R115777. Methodology, structure activity relationships, and pharmacology will be presented. R115777 is currently in phase III clinical evaluation.

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Section: Introductionmentioning

confidence: 99%

Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery

Venet¹,

End²,

Angibaud

2003

CTMC

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“…[2-4] In the ‘CAAX’ box, A represents any aliphatic amino acid and X represents the residue that controls farnesylation or geranylgeranylation. [5, 6] The prenylation modification serves to direct membrane association of many proteins including members of the Ras superfamily of proteins. [7] It has been previously shown that the K-Ras protein is involved in approximately 30% of all human cancers and inhibition of the farnesylation of Ras abolishes its oncogenic activity.…”

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confidence: 99%

Evaluation of a cell penetrating prenylated peptide lacking an intrinsic fluorophore via in situ click reaction

Ochocki

Mullen

Wattenberg

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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Protein prenylation involves the addition of either a farnesyl (C15) or geranylgeranyl (C20) isoprenoid moiety onto the C-terminus of many proteins. This natural modification serves to direct a protein to the plasma membrane of the cell. A recently discovered application of prenylated peptides is that they have inherent cell-penetrating ability, and are hence termed cell penetrating prenylated peptides. These peptides are able to efficiently cross the cell membrane in an ATP independent, non-endocytotic manner and it was found that the sequence of the peptide does not affect uptake, so long as the geranylgeranyl group is still present. The present study investigates the effect of removing the fluorophore from the peptides and investigating the uptake by confocal microsopy and flow cytometry. Our results show that the fluorophore is not necessary for uptake of these peptides. This information is significant because it indicates that the prenyl group is the major determinant in allowing these peptides to enter cells; the hydrophobic fluorophore has little effect. Moreover, these studies demonstrate the utility of the Cu-catalyzed click reaction for monitoring the entry of nonfluorescent peptides into cells.

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Structures of Protein Farnesyltransferase

Cited by 2 publications

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Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery

Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery

Evaluation of a cell penetrating prenylated peptide lacking an intrinsic fluorophore via in situ click reaction

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Structures of Protein Farnesyltransferase

Cited by 2 publications

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Farnesyl Protein Transferase Inhibitor ZARNESTRA&#8482; R115777 - History of a Discovery

Farnesyl Protein Transferase Inhibitor ZARNESTRA&#8482; R115777 - History of a Discovery

Evaluation of a cell penetrating prenylated peptide lacking an intrinsic fluorophore via in situ click reaction

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Product

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Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery

Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery