Inhibition of farnesyltransferase: A rational approach to treat cancer?

Puntambekar, Devendra S; Giridhar, Rajani; Yadav, Mange Ram

doi:10.1080/14756360601072841

Cited by 7 publications

(5 citation statements)

References 95 publications

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“…Protein farnesyltransferase (FTase) is a two-subunits heterodimeric zinc enzyme that is comprised by a 48 kDa -subunit and a 46 kDa -subunit [1][2][3][4], and that has been for the past decade at the very heart of the development of a promising new class of biologically active drugs -the farnesyltransferase inhibitors (FTIs) -whose precise target, mechanism of action, and biological and clinical significance are still a matter of dispute [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Sousa

Fernandes²,

Ramos³

2008

CMC

108

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Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of particular attention in anti-cancer research. This enzyme promotes the addition of a farnesyl group from farnesyl diphosphate (FPP) to a cysteine residue of a protein substrate containing a typical -CAAX motif at the carboxyl terminus. Initial interest in FTase inhibition was prompted by the finding that farnesylation was absolutely required for the oncogenic forms of ras proteins to transform cells, as ras proteins have been implicated in around 30% of all human cancers. This discovery led to frenetic search for FTase inhibitors (FTIs), with more than 400 patents registered in less than a decade. However, despite the very promising initial results, the outcome of Phase II and Phase III clinical trials was, is general, rather disappointing, with the most advanced FTIs failing to demonstrate anti-tumor activity in ras dependent cancers, presumably because K-ras, the most frequently mutated form of ras in human cancers, is able to bypass FTI blockade through cross-prenylation by the related enzyme geranylgeranyltransferase I (GGTase I). Surprisingly, several of these compounds were later shown to have anti-tumor activity against non-ras dependent cancers, launching the grounds for a new and exciting era in FTIs research and development, although the precise target for the FTIs activity of these compounds still remains unknown. This review reports the recent progress in the field, presenting a comprehensive summary of the most promising FTIs, in terms of their chemical structure and properties, taking into account the topology of the enzyme's active-site, and the most recent mechanistic results on the catalytic activity of FTase, both at the theoretical and mechanistic level. These features are presented in close linking with the available results on the biological activity of these inhibitors, and with the outcome of the most recent clinical trials.

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Section: Introductionmentioning

confidence: 99%

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Sousa

Fernandes²,

Ramos³

2008

CMC

108

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“…The IC 50 and K i values are relatively high (IC 50 58.03 μM/K i 4.40 µM for human and IC 50 45.96 μM/K i 3.16 µM for C. elegans FTase). Lonafarnib and tipifarnib, the most prominent FTIs, show 24000 times lower IC 50 values of 1.9 nM and 0.86 nM, respectively ( Curtin et al, 2003 ; Puntambekar et al, 2007 ). These FTIs are not competitive inhibitors against FPP like Manumycin A, but against the CAAX substrate.…”

Section: Discussionmentioning

confidence: 99%

Analyzing the postulated inhibitory effect of Manumycin A on farnesyltransferase

Hagemann

Altrogge²,

Kehrenberg³

et al. 2022

Front. Chem.

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Manumycin A is postulated to be a specific inhibitor against the farnesyltransferase (FTase) since this effect has been shown in 1993 for yeast FTase. Since then, plenty of studies investigated Manumycin A in human cells as well as in model organisms like Caenorhabditis elegans. Some studies pointed to additional targets and pathways involved in Manumycin A effects like apoptosis. Therefore, these studies created doubt whether the main mechanism of action of Manumycin A is FTase inhibition. For some of these alternative targets half maximal inhibitory concentrations (IC50) of Manumycin A are available, but not for human and C. elegans FTase. So, we aimed to 1) characterize missing C. elegans FTase kinetics, 2) elucidate the IC50 and Ki values of Manumycin A on purified human and C. elegans FTase 3) investigate Manumycin A dependent expression of FTase and apoptosis genes in C. elegans. C. elegans FTase has its temperature optimum at 40°C with KM of 1.3 µM (farnesylpyrophosphate) and 1.7 µM (protein derivate). Whilst other targets are inhibitable by Manumycin A at the nanomolar level, we found that Manumycin A inhibits cell-free FTase in micromolar concentrations (Ki human 4.15 μM; KiC. elegans 3.16 μM). Furthermore, our gene expression results correlate with other studies indicating that thioredoxin reductase 1 is the main target of Manumycin A. According to our results, the ability of Manumycin A to inhibit the FTase at the micromolar level is rather neglectable for its cellular effects, so we postulate that the classification as a specific FTase inhibitor is no longer valid.

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“…This lipidation step is critical for localization to membranes of cell compartments, where such modified proteins function . Human FTase (hFTase) has long been the target for the development of cancer therapeutics, which presents an opportunity for repurposing reagents discovered in these studies, provided that these inhibit fungal and not human enzymes . Structural studies of FTases from fungal pathogens have revealed significant differences between the human and fungal enzymes in substrate‐ and product‐binding regions, which can be exploited for the discovery of species‐specific FTase inhibitors .…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Human FTase (hFTase) has long been the target for the development of cancer therapeutics, which presents an opportunity for repurposing reagents discovered in these studies, provided that these inhibit fungal and not human enzymes. 11,[13][14][15][16][17][18][19][20] Structural studies of FTases from fungal pathogens have revealed significant differences between the human and fungal enzymes in substrate-and product-binding regions, which can be exploited for the discovery of species-specific FTase inhibitors. [20][21][22][23][24][25][26][27] Here we report the structure of FTase from the fungal pathogen Aspergillus fumigatus (AfFTase) and show that this enzyme also exhibits structural differences from the human enzyme that are sufficient for species-specific inhibition.…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of the fungal pathogen Aspergillus fumigatus protein farnesyltransferase complexed with substrates and inhibitors reveal features for antifungal drug design

et al. 2014

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Species of the fungal genus Aspergillus are significant human and agricultural pathogens that are often refractory to existing antifungal treatments. Protein farnesyltransferase (FTase), a critical enzyme in eukaryotes, is an attractive potential target for antifungal drug discovery. We report high-resolution structures of A. fumigatus FTase (AfFTase) in complex with substrates and inhibitors. Comparison of structures with farnesyldiphosphate (FPP) bound in the absence or presence of peptide substrate, corresponding to successive steps in ordered substrate binding, revealed that the second substrate-binding step is accompanied by motions of a loop in the catalytic site. Re-examination of other FTase structures showed that this motion is conserved. The substrate-and product-binding clefts in the AfFTase active site are wider than in human FTase (hFTase). Widening is a consequence of small shifts in the a-helices that comprise the majority of the FTase structure, which in turn arise from sequence variation in the hydrophobic core of the protein. These structural effects are key features that distinguish fungal FTases from hFTase. Their variation results in differences in steady-state enzyme kinetics and inhibitor interactions and presents opportunities for developing selective anti-fungal drugs by exploiting size differences in the active sites. We illustrate the latter by comparing the interaction of ED5 and Tipifarnib with hFTase and AfFTase. In AfFTase, the wider groove enables ED5 to bind in the presence of FPP, whereas in hFTase it binds only in the absence of substrate. Tipifarnib binds similarly to both enzymes but makes less extensive contacts in AfFTase with consequently weaker binding.

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Inhibition of farnesyltransferase: A rational approach to treat cancer?

Cited by 7 publications

References 95 publications

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Analyzing the postulated inhibitory effect of Manumycin A on farnesyltransferase

Crystal structures of the fungal pathogen Aspergillus fumigatus protein farnesyltransferase complexed with substrates and inhibitors reveal features for antifungal drug design

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