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Peptidomimetic Inhibitors of Ras Farnesylation and Function in Whole Cells

Peptidomimetic Inhibitors of Ras Farnesylation and Function in Whole Cells

A M Garcia, C Rowell, K Ackermann, J J Kowalczyk, M D Lewis

J Biol Chem. 1993 Sep 5;268(25):18415-8.

PMID: 8360140

Abstract:

The ras protooncogene is involved in regulation of cell growth. Mutations that activate the protein result in uncontrolled cell growth. Ras undergoes a series of posttranslational processing events, the first of which, farnesylation, is crucial for the function of the protein. Inhibitors of the farnesyltransferase enzyme are therefore potential candidates for the development of anticancer drugs. Tetrapeptides have been reported to be good inhibitors of this enzyme in vitro. We have synthesized analogs of the tetrapeptide Cys-Val-Phe-Met by replacement of the amino-terminal amide bonds. One inhibitor, B581, is permeable to the cell membrane. In the cell, it inhibits processing of two farnesylated proteins, H-ras and lamin A, but it does not inhibit processing of a geranylgeranylated protein, Rap 1A. Microinjection of B581 into frog oocytes inhibits maturation induced by activated, farnesylated H-ras but not maturation induced by activated, geranylgeranylated H-ras or by progesterone. These results demonstrate that this peptide mimic inhibits farnesylation selectively in the cell. The inhibition of farnesylation results in inhibition of H-ras function.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP149759966	B581		149759-96-6	Price

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