Ras function inhibitors

Roberts, M.J., et al. (2006). Hydrophilic anihnogeranyl diphosphate prenyl analogues Are Ras function inhibitors. Biochemistry 45 15862-15872. 

Although FTase inhibitors influence the farnesylation of Ras they are likely to interfere with the posttranslational modifications of other CAAX-containing proteins as well. Apart from the approximately 20 farnesylated proteins that are known today, farnesylation is also required for normal Ras function which in turn is critical for normal cell viability. For these reasons farnesyltransferase... 

To function, Ras must be attached to the plasma membrane. Translocation from the cytoplasm to membrane requires a series of posttranslational modifications that begin with farnesylation of the cysteine residue, the fourth amino acid residue from the C terminus of the protein, by famesyl protein transferase (FPTase) (64). Attachment of the hydrophobic 15-carbon lipid farnesyl group allows Ras molecule insertion into the plasma membrane and is crucial for Ras signaling activity and transformation properties. As farnesylation is required for oncogenic Ras function, FPTase inhibitors (FTIs) are obvious candidate antineoplastic agents. Several drugs that inhibit Ras farnesylation are at various stages of clinical development (65). 

Interestingly, members of the Faller laboratory demonstrated that chronic PMA treatment of mouse fibroblasts, which depletes PKC activation, caused a K-Ras-dependent apoptotic mechanism [10] that was not well suppressed by the apoptotic inhibitor Z-VADfmk [11]. Thus, any deregulation of PKC activity, whether stimulation or suppression, may alter K-Ras control of cell survival in a context-dependent manner, either directly or indirectly, further highlighting the complexity of interfering in Ras function in a controllable way. 

The popular garden plant Tabernaemontana divaricata which is extensively grown in gardens in Malaysia as well as in India provided several novel bisindoles, one of which, viz., conophylline (303) has been shown to be a potent inhibitor of ras functions (vide infra). There are two distinct varieties, the single flower variety produces both conophylline (303) and conophyllidine (304) [137,180] while the double flower variety gives in addition, a third dimeric alkaloid, conofoline (305) [ 138] as well as several new aspidosperma-type compounds. 

Famesyltransferase inhibitors as potential anticancer drugs In 1989, it was discovered that famesylation of a cysteine residue near the ras gene protein s C-terminus is required for its biological activity. Interfering with Ras function by blocking the enzyme responsible for its... 

We showed that compactin induces normal phenotypes in K-ras S-NRK cells and K-ras-NIH3T3 cells. Addition of compactin for 3 days induced normal morphology and actin filament organization in K-ras -NRK cells at the permissive temperature. Western blotting analysis showed that fibronectin expression was increased by compactin in both K-ras S-NRK and K-ras-NIH3T3 cells. These cellular effects of compactin were completely blocked by 100 jlM mevalonate. Compactin inhibited the growth of ras-expressing cells more effectively than that of their counterpart normal cells. Thus, inhibitors of mevalonate synthesis suppress Ras functions in cell culture. 

The protein Ras, an important intracellular signal transducer, is crucially involved in the development of tumor growth. The farnesylation of Ras, catalyzed by the enzyme Ras-farnesyl-transferase, is essential to its proper functioning in the normal and in the transformed state. Therefore, the inhibition of Ras lipidation has become a promising target for the development of new classes of anti-tumor agents. This review focuses on the different classes of Ras-farnesyl-transferase inhibitors and compares their biological properties and modes of action in vitro as well as in vivo. 

In order for Ras to function properly, the protein must be localized to the plasma membrane. This is achieved by the addition of a farnesyl group to a cysteine residue near the carboxy terminus, which then acts as a tether to the cellular membrane. Farnesyl transferase, the enzyme that adds the farnesyl moiety to Ras, is also a target for small-molecule intervention. This class of inhibitors is the subject of another chapter (Angibaud et al, in this volume). 

Dissociation of GDP may be inhibited by specific proteins known as guanine nucleotide dissociation inhibitors (GDI). Proteins with this function are foimd in all members of the Ras family (see Chapter 9). The GDIs have the function, above aU, to provide a cytosohc pool of inactive, GDP-bound proteins (see Chapter 9.1). 

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