Inhibition of farnesyltransferase

Details Inhibition of farnesyltransferase Inhibition of farnesyltransferase

1995-06-05

1999-01-05

Tsang, Cecilia J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 18, 514 7, 530331, A61K 3800

Patent

active

058563105

ABSTRACT:
Peptidomimetics of the formula C-AMBA-X where C is cysteine, X is, for example, methionine or phenylalanine and AMBA is a hydrophobic spacer, notably 3-aminomethylbenzoic acid. These compounds are effective inhibitors of p21ras farnesyltransferase. Other modifications including alternative spacers for AMBA, and replacement of the A.sub.1 A.sub.2 X component of known CA.sub.1 A.sub.2 X tetrapeptides by a non-peptide aryl or heterocyclic component are also disclosed as are various phosphorylated and arylated derivatives of peptides and peptidomimetics. Pro-drugs made by functionalizing terminal amino and carboxylic acid groups of peptides and peptidomimetics are also disclosed. Such functionalized derivatives demonstrate increased cell uptake. Other structural modifications are also referred to.

REFERENCES:
patent: 5043268 (1991-08-01), Stock
patent: 5141851 (1992-08-01), Brown
patent: 5238922 (1993-08-01), Graham et al.
Hancock et al, "A polybasic Domain or Palmitoylation is Required in Addition to the CAAX Motif to Localize p 21.sup.ras to the Plasma Membrane", Cell, vol. 63, Oct. 5, 1990 pp. 133-139.
Reiss et al, "Inhibition of Purified p21.sup.ras Farnesyl:Protein Transferase by Cys-AAX Tetrapeptides", Cell, vol. 62, Jul. 13, 1990, pp. 81-88.
Willumsen et al, "The p21 ras C-terminus is required for transformation and membrane association," Nature, vol. 310, Aug. 16, 1984, pp. 583-586.
Harde, Bioorg Med Chem Lett 4, 273, 1994.
Farrington, Arch Bioch Biophys 307, 165, 1993.

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