Figure 20.18 Structural features of some protein kinase inhibitors. The reader is referred to the original reference (Patrick and Heimbrook, 1996) and the text for further details. (Adapted from Patrick and Heimbrook, 1996, with permission of the authors and publisher.)

bers of this pathway. The example from Figure 20.18 is PD 98059, which inhibits both the MEK-kinase or raf-dependent activation of MEK but does not seem to affect raf autophosphorylation (cf. Patrick and Heimbrook, 1996). In addition to inhibitors of signal transduction kinases, there are also being developed chemotherapeutic agents capable of altering the function of cyclin-dependent kinase inhibitors that may have important usefulness in chemotherapy (Kaubisch and Schwartz, 2000). Despite the extensive work in this area and the large involvement of protein kinase activities in signal transduction pathway, one must remember that all of these pathways function in normal cells, and thus the differential between effective treatment in neoplasia and lack of toxicity in normal tissues (therapeutic index, see above) may be less than desired in many instances.

Protein Prenylation as a Target for Chemotherapy -g

As noted in Figure 20.17, the ras protein is shown bound to the plasma membrane through a lipid %

moiety, farnesyl, which is covalently linked to a cysteine sulfhydryl of the protein, forming a thioether bond. As briefly discussed in Chapter 7, this interaction of these G proteins with the cell membrane is required for normal signal transduction. Inhibitors of the formation of isoprenoids, especially farnesyl and geranyl moieties and/or their linkage to the protein, can result in inhibition of signal transduction pathways. This has been demonstrated by the rational design of pepti- | domimetics of the carboxyl terminal tetrapeptide farnesylation site on ras (Lerner et al., 1997; Moasser et al., 1998). The resulting agents are capable of inhibiting ras processing, selectively antagonizing oncogenic signaling, and suppressing neoplastic growth in mouse models with relatively small side effects. While there are a number of key problems that still must be overcome in

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