FPTase inhibitor structures

To identify FPTase inhibitors traditional sources of samples (chemical sample collections, natural product and combinatorial chemistry libraries) were randomly screened with varying degrees of success. Tetrapeptides that were structurally similar to the CaaX-box motif were almost immediately discovered as being both relatively potent inhibitors and efficient substrates of the enzyme. These initial peptide leads led to the formation of a number of medicinal chemistry teams whose primary objectives were to convert these tetrapeptides into non-peptidic... 

Cembranolide, a diterpene, is unique in that it is the only FPTase inhibitor isolated from a marine specimen, Lobophytum cristagalli (Order Alcyonacea, Family Alcyoniidae), that was collected at a 15m depth from Seychelles Island. The compound was isolated by silica gel chromatography followed by reverse phase HPLC and the structure of this 14/5-bicyclic diterpenoid (Figure 24) was elucidated by NMR and confirmed by X-ray crystallography [115]. 

Similar to cembranolide, clavaric acid was competitive with respect to the Ras-peptide substrate Kj = 1.4 jM) and non- and/or un-competitive with FPP despite having a negatively charged carboxyl group. This is only the second example of a non-nitrogenous FPTase inhibitor that is competitive with peptide substrate. These two (cembranolide and clavaric acid) structurally distinct compounds show remarkably similar profiles of the mechanism of FPTase inhibition [117]. 

Banyu Pharmaceutical Company reported that J-104134 (Figure 7) was a potent inhibitor of rat FPTase activity (IC50 = 5 nM). This compound, though structurally similar to many FPP competitive natural product inhibitors (vide infra), contain multiple free carboxyl groups but, surprisingly, unlike the natural product inhibitors, was active in cell-based assays (IC50 = 4.3 jiM) [63]. 

Pfizer reported the discovery of a new class of structurally complex alkyl carboxylic acids, as exemplified by CP-225917 and CP-263114 (Figure 20), that are weak and non-selective inhibitors of squalene synthase and FPTase. These compounds were isolated by acid base liquid-liquid partition, Sephadex LH20 chromatography and reverse phase HPLC from ethyl acetate extracts of an unidentified fungus that also produced zaragozic acid A [97]. 

Although rhombenone inhibited partially purified rat brain FPTase (IC50 = 2.3 pM), other dammaranes, for example, protopannaxydiol and protopannaxytriol, that possess a C-27 methyl group and lack other structural features of rhombenone, were weakly active as inhibitors of... 

Both the mixed stems and stem bark, and the stems CHCls-soluble extracts of L. wallichii Kurz, were found to display significant inhibitory activity in a famesyl protein transferase (FPTase) assay system. It has been suggested that inhibitors of this enzyme may be considered as potential anticancer agents for tumors in which products of the ras oncogene contribute to transformation. The bioassay directed fractionation of the two active extracts [213] led to the isolation of the known lupane lactones, ochraceolide A (128), ochraceolide B (129), and the new compound dihydroochraceolide A (135), among other known triterpenes. The structure of 135 was confirmed by reduction of 128, Fig. (37) and the stereochemistry to the epoxide group of 129, not determined when this compound was first isolated from K. ochracea [211], was established by preparation of both epoxide isomers, 129 and the new semisynthetic derivative, 20-epi-ochraceolide B (136) from 128. 

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