The acquisition ofdetailed kinetic information about the FTase reaction and the physi-cochemical nature ofFTase substrates has ledto the rational design ofFTIs (1—7). Three general approaches have been used:
1. The design and synthesis of farnesyl diphosphate (FDP) analogs that compete with the substrate FDP for FTase;
2. Peptidomimetics or CAAX mimetics that compete with the CAAX portion of Ras for FTase; and
3. Bisubstrate analogs that combine the features of both FDP analogs and peptidomimetics
Still other approaches have resulted in the development of several types of structurally and functionally unrelated compounds that are nonpeptidomimetics of FTase. The recent elucidation of the crystal structure of FTase most likely will further our understanding of the binding of specific classes of inhibitors and provide insight into the optimal design of FTIs (8).
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