FDP Analogs

Over the past decade, a number of structurally diverse molecules have been isolated that have demonstrated specific activity against FTase. These compounds have been identified asaresult oftwo drug discovery strategies: 1) high-throughput screening ofnatural products or libraries; and 2) rational principles of drug design. The former approach has identified several natural products that are competitive inhibitors of FDP, including chaeto-mellic acids andmanumycin analogs (9-12,14,15). These compounds selectively inhibit FTase, with substantially less inhibitory activity against GGTase I, and have potencies in the submicromolar to micromolar range (1,16). The affinity of manumycin for FTase is 10 times less than FDP, however, it also inhibits the growth ofseveral human pancreatic cancer cell lines, with IC50s ranging from 3.5-7.5 |mol/L (17). One ofthe manumycin analogs, UFC1-C was shown to inhibit the growth of K-Ras-transformed fibrosarcoma at a dose of 6.3 mg/kg, administered intraperitoneally (i.p.) for 5 d from d 0 to d 4; however, inhibition of FTase in mammalian cells has not been directly demonstrated, and thus

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