Prenyl transferase inhibitors
AssigneeWayne State University
InventorRichard A. Gibbs
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Abstract
Farnesyl diphosphate analogs, specifically the 3-substituted alcohol precursors of the diphosphate analogs, 3-allylfarnesol and 3-vinylfarnesol, are potent inhibitors of mammalian protein fanesyltransferase (FTase). 3-allylgeranylgeraniol is a highly specific cellular inhibitor of protein geranylgeranylation (GGTase I). Furthermore, these compounds are able to efficiently block the anchorage-dependent growth of ras transformed cells. While 3-allylfarnesol inhibits protein farnesylation in situ, 3-vinylfarnesol instead leads to the abnormal prenylation of proteins with the 3-vinylfarnesyl group. In a similar manner, treatment with 3-allylgeranylgeraniol inhibits protein geranylgeranylation while 3-vinylgeranylgeraniol restores protein geranylgeranylation in cells.
Claims12
The compound which is 7-allyfarnesol.
The compound which is para-biphenylfarnesol.
The compound which is 3-allylfarnesol.
The compound which is 3-isopropylfarnesol.
The compound which is 3-isopropylfarnesyl diphosphate.
The compound which is 3-allyl geranylgeranyl diphosphate.
A method for reducing the level of protein farnesylation in mammalian cells in a mammalian host, wherein said cells are sensitive to treatment with a compound selected from the group consisting of 3-vinyl farnesol, 3-allylfarnesol, 3-isopropylfarnesol, 3-vinyl geranylgeraniol, and 3-allylgeranylgeraniol;
- the said method comprising administering to said mammalian host an amount of the compound effective to inhibit the activity of farnesyl protein transferase;
- wherein the activity of farnesyl protein transferase is reduced.
A method for reducing the level of protein geranylgeranylation in mammalian cells in a mammalian host, wherein said cells are sensitive to treatment with a compound with the formula:
- wherein R is a C2-C10 saturated or unsaturated alkyl, aryl, cycloalkyl, or C6-C10 aromatic or heteroaromatic group, and X is —OH or —P2O7;
- the said method comprising administering to said mammalian host an amount of the compound effective to inhibit the activity of geranylgeranyl protein transferase;
- wherein the activity of geranylgeranyl protein transferase is reduced.
A compound of the general formula:
- wherein R is selected from the group consisting of unsaturated isomers of propyl, butyl (exclusive of tert-butyl), and pentyl, cyclopentyl, and heterosubstituted moieties selected from the group consisting of fluorophenyl, (trimethylsilyl)methyl, 1-ethoxyvinyl, and 2-furanyl, 2-thiophenyl, and X is —OH or —P2O7.
A compound of the general formula:
- wherein R is selected from the group consisting of unsaturated isomers of propyl, butyl (exclusive of tert-butyl), and pentyl, cyclopentyl, and heterosubstituted moieties selected from the group consisting of fluorophenyl, (trimethylsilyl)methyl, 1-ethoxyvinyl, and 2-furanyl, 2-thiophenyl, and X is —OH or —P2O7.
A method of inhibiting restenosis by administering an effective amount of 3-allyl or 3-vinyl geranylgeraniol to a patient following cardiac catheterization or angioplasty.
Dependencies are inferred from the claim text.