Inhibitors of farnesyl-protein transferase

Details Inhibitors of farnesyl-protein transferase Inhibitors of farnesyl-protein transferase

1994-09-29

1996-12-17

Scheiner, Toni R.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 18, 530330, 530331, 560 13, 560 16, 558302, 562426, C07K 500, C07K 700, C07K 1700, A61K 3800

Patent

active

055853595

ABSTRACT:
The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras farnesyl transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

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Gibbs, J. B., et al. "Selective Inhibition of Farnesyl-Protein Transferase Blocks Ras Processing in Vivo", The Journal of Biological Chemistry, vol. 268, No. 11, pp. 7617-7620 (1993).
Goldstein, J. L. et al., "Nonfarnesylated Tetrapeptide Inhibitors of Protein Farnesyltransferase", The Journal of Biological Chemistry, vol. 266, No. 24 pp. 15575-15578 (1991).
James, G. L. et al., "Benzodiazepine Peptidomimetic BZA-5B Interrupts the MAP Kinase Activation Pathway in H-Ras-transformed Rat-1 Cells, but Not in Untransformed Cells", The Journal of Biological Chemistry, vol. 369, No. 44, pp. 27705-27714 (1994).
James, G. L. et al., "Benzodiazepine Peptidomimetics: Potent Inhibitors of Ras Farnesylation in Animal Cells", Science, vol. 260, pp. 1937-1942 (1993).
Kohl, N. E. et al., "Selective Inhibition of ras-Dependent Transformation by a Farnesyltransferase Inhibitor", Science, vol. 260, pp. 1934-1937 (1993).
Kohl, N. E. et al., "Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice", Proc. Natl. Acad. Sci. USA, Med. Sciences, vol. 91, pp. 9141-9145 (1994).
Pompliano, D. L., "Steady-State Kinetic Mechanism of Ras Farnesyl:Protein Transferase", Biochemistry, vol. 31, pp. 3800-3807 (1992).
Lorenzino, L. S. et al., "A peptidomimetic Inhibitor of Farnesyl:Protein Transferase Blocks the Anchorage-dependent and -independent Growth of Human Tumor Cell Lines," Cancer Research, 55, pp. 5302-5309 (1995).
Document Number 07/968,022, Inventor Merck et al , Filing Date Oct. 29, 1992.
Document Number 08/143,943, Inventor Merck et al , Filing Date Oct. 27, 1993.

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