Tetrapeptide-based inhibitors of farnesyl transferase

Details Tetrapeptide-based inhibitors of farnesyl transferase Tetrapeptide-based inhibitors of farnesyl transferase

1992-04-03

1995-05-30

Cashion, Jr., Merrell C.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

8 to 10 amino acid residues in defined sequence

530329, 530330, A61K 3700, A61K 3702, C07K 500, C07K 700

Patent

active

054202450

ABSTRACT:
Disclosed are methods and compositions for the identification, characterization and inhibition of mammalian farnesyl protein transferases, enzymes involved in the farnesylation of various cellular proteins, including cancer related ras proteins such as p21.sup.ras. One farnesyl protein transferase which is disclosed herein exhibits a molecular weight of between about 70,000 and about 100,000 upon gel exclusion chromatography. Also disclosed are methods and compositions for the preparation of farnesyl transferase by recombinant means, following the molecular cloning and co-expression of its two subunits, for assay and purification of the enzyme, as well as procedures for using the purified enzyme in screening protocols for the identification of possible anticancer agents which inhibit the enzyme and thereby prevent expression of proteins such as p21.sup.ras. Also disclosed is a families of compounds which act either as false substrates for the enzyme or as pure inhibitors and can therefore be employed for inhibition of the enzyme. The most potent inhibitors are ones in which phenylalanine occurs at the third position of a tetrapeptide whose amino terminus is cysteine.

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