[Inhibitors of isoprenylation of ras p21].

Posttranslational modification and membrane localization are critical for the function of products of ras oncogenes which are frequently founded to be mutated in human tumors. Farnesylation by farnesyltransferase (FTase) is the first and obligatory step in the processing of ras p21, and FTase has attracted attention as a new target of anticancer agents. Many FTase inhibitors have been identified or synthesized in random screening, and studies on FPP analogs, CAAX analogs, and bisubstrate analogs. These inhibitors induced flat reversion and inhibited the anchorage-independent growth of ras transformant and ras-mutated human tumor cells through the inhibition of posttranslational modification of ras p21. B1086, L-739,749, L-744,832 and FTI-276, which are CAAX analogs, were reported to show inhibition of tumor growth in ras-mutated human tumor xenograft models and to induce regression of mammary and salivary carcinoma in ras transgenic mouse model. FTase inhibitors have the potential to be developed as therapy for ras-mutated human tumors. On the other hand, it has been reported that K-ras 4B p21 could be modified by geranylgeranyltransferase (GGTase). Therefore, GGTase inhibitors have also been evaluated in addition to FTase inhibitors.