Therapeutic interest in farnesyltransferase inhibitors (FTIs) historically grew out of a desire to target the ras oncogene. Roughly 30% ofall human tumors possess a mutation in one of the ras proto-oncogenes. These mutations result in guanosine triphosphate (GTP) becoming permanently bound to Ras, resulting in uncontrolled cellular proliferation. Some tumor types, namely pancreatic and colon cancers, are especially refractory to conventional chemotherapy and exhibit a particularly high incidence of activating ras mutations (approx 90 and 50%, respectively). Interest in farnesyltransferase (FTase) arose because this enzyme represented a potential target for interfering with Ras function. Ras must be anchored to the plasma membrane to act as a transducer of signaling events. Because it has no transmembrane domain, Ras is post-translationally modifed by FTase, thereby acquiring a farnesyl group and consequently the requisite hydrophobicity for membrane attachment. The rationale for FTase as an anticancer drug target has been comprehensively reviewed elsewhere (1-3).

During the past year, FTIs have entered into the early stages of clinical testing (4). Without a clinically approved predecessor, a number ofcritical issues require resolution before the ideal properties of an FTI can be determined. For example, what degree of selectivity for FTase relative to other prenylation enzymes, namely geranylgeranyltransferases,

From: Farnesyltransferase Inhibitors in Cancer Therapy Edited by: S. M. Sebti and A. D. Hamilton © Humana Press Inc., Totowa, NJ

Fig. 1. Chemical structures of key compounds.

needs to be achieved? The finding that K-Ras is geranylgeranylated when farnesylation is shut down does not make this a straightforward question (5). The existence of normal cellular farnesylated proteins, such as G-proteins involved in visual signal transduction and endogenous Ras, also raises the issue of whether FTIs will prove toxic based on mechanistic considerations. Mounting preclinical evidence suggests that this will not be the case (6,7).

The vast majority ofresearch devotedto the development ofefficacious FTI drug candidates has purposely focused on the CAAX binding region of FTase. The existing bias against farnesyl diphosphate (FPP) analogs stems largely from their potential for toxicity based on the ubiquitous role played by FPP in cellular metabolism. However, FPP-com-petitive inhibitors need not be FPP analogs. The studies to be described below provide evidence that one class of FPP-competitive FTIs, the histidylbenzylglycinamides, exhibit promising preclinical activity against multiple human tumor xenograft models.

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