Compounds for inhibition of proteolysis

Details Compounds for inhibition of proteolysis Compounds for inhibition of proteolysis

1995-02-13

1998-08-04

Johnson, Jerry D.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

15 to 23 amino acid residues in defined sequence

530330, 530331, 514 13, 514 18, A61K 3803

Patent

active

057895414

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to controlling neoplastic cell growth. This invention is supported by NIH Grant No. EY03624 and the government has certain rights to the invention.
Activated ras genes have been associated with a number of human cancers. An activated ras gene, H-ras-1, was the first non-viral oncogene discovered. Several other human ras proto-onco genes have subsequently been identified including H-ras-2, K-ras-1, K-ras-2, and N-ras. For each of these ras genes several activated mutant forms have been identified. Activated K-ras genes have been detected in pre-malignant neoplasms of the human colon and in human pre-leukemia.
The ras proteins, and ras-like proteins, as well as other proteins such as signal transducing G proteins, have a conserved carboxyl-terminal -CAAX motif (C=cysteine, A=aliphatic amino acid, and X=any amino acid)(SEQ ID No. 3). This motif is involved in a series of post-translational modifications including polyisoprenylation carboxyl-terminal proteolysis, and carboxyl-methylation. A number of ras-related small GTP binding proteins including R-ras, RAS2, rap-2, and phoB also have a carboxyl-terminal -CAAX motif, and it has been suggested that these proteins may be post-translationally modified in the same manner (Hancock et al., Cell 57:1167, 1989). Among ras proteins, H-ras, N-ras (Gutierrez et al., EMBO J., 8:1093, 1989) and K-ras (Hancock et al., Cell, 57:1167, 1989) undergo polyisoprenylation, carboxyl-terminal proteolysis and carboxyl-methylation. Inhibition of these modifications by mutation of Cys.sup.186 to Ser blocks both membrane localization of ras gene product and transformation of the cell (Willumsen et al., EMBO J. 3:2581; Gutierrez et al., EMBO J. 8:1093, 1989).
A number of other proteins which have a carboxyl-terminal -CAAX motif including the .gamma.-subunit of transducing (Lai et al., Proc. Natl. Acad. Sci. USA, 87:7673, 1990), yeast mating factor mata (Anderegg et al., J. Biol. Chem., 263:18236, 1988), and nuclear lamin B (Chelsky et al., J. Biol. Chem., 262:4303, 1987; Farnsworth et al., J. Biol. Chem., 264:20422, 1989; Vorburger et al., EMBO J., 8:4007, 1989) have also been shown to undergo polyisoprenylation, carboxyl-terminal proteolysis, and carboxyl-methylation.
Analysis of in vitro translated K-ras demonstrated,d that farnesylated, non-proteolysed, non-methylated K-ras associates inefficiently with cell membranes. Removal of the carboxyl-terminal three amino acids of this K-ras product increases membrane binding 2-fold, and methylation of the K-ras product increases membrane binding another two-fold (Hancock et al., EMBO J. 10:641 1991).
Mevinolin inhibits cellular synthesis of mevalonic acid; this leads to depletion of polyisoprenoids and is expected to interfere with polyisoprenylation reactions. Mevinolin affects post-translational processing of ras proteins and interferes with ras membrane localization (Hancock et al., Cell 57:1167, 1989). In addition, cells treated with mevinolin are blocked in cell growth in the G1 phase and the G2/M phase (Maltese et al., J. Cell Physiol. 125:540, 1985). It has been proposed that this growth arrest, which is associated with the inhibition of mevalonate incorporation into polypeptides but not other isoprenoid derivatives such as cholesterol (Sinensky et al., Proc. Natl. Acad. Sci. USA, 82:3257, 1985), is caused by disruption of nuclear lamin B function (Beck et al., J. Cell. Biol., 107:1307, 1988). The observation that mevinolin interferes with post-translational modification of the ras gene product combined with involvement of activated ras genes in human malignancies has led to the suggestion that mevinolin or derivatives of mevinolin may prove to be novel cytotoxic/static agents or even a starting point for the development of an anti-ras drug (Hancock et al., Cell 57:1167, 1989).
Hancock et al. (EMBO J. 10:641, 1991) report that a proteolytic activity capable of removing the -AAX motif of p21.sup.K-ras(B) is associated with microsomal membranes.
Ashby et al. (Proc. Nat'1. Acad. Sci. U

REFERENCES:
Tan et al., J. Am. Chem. Society (113), pp. 6299-6300, Jul. 31, 1991.
Hancock et al., Cell 57:1167, 1989.
Gutierrez et al., EMBO J. 8:1093, 1989.
Willumsen et al., EMBO J. 3:2581 (date unknown) .
Lai et al., Proc. Nat'l. Acad. Sci. USA 87:7673, 1990.
Anderegg et al., J. Biol. Chem. 263:18236, 1988.
Chelsky et al., J. Biol. Chem. 262:4303, 1987.
Farnsworth et al., J. Biol. Chem. 264:20422, 1989.
Vorburger et al., EMBO J. 8:4007, 1989.
Hancock et al., EMBO J. 10:641, 1991.
Maltese et al., J. Cell Physiol. 125:540, 1985.
Sinensky et al., Proc. Nat'l. Acad. Sci. USA 82:3257, 1985.
Beck et al., J. Cell Biol. 107:1307, 1988.
Ashby et al., Proc. Nat'l. Acad. Sci. USA 89:4613, 1992.
Walter et al., Meth. Enzym. 96:84, 1983.
Perez-Sala et al., Proc. Nat'l. Acad. Sci. USA 88:3043, 1991.
Trepman et al., Arch. Biochem. Biophys. 204:524, 1980.

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