C-Terminal Modifications of Histidyl-<i>N</i>-benzylglycinamides To Give Improved Inhibition of Ras Farnesyltransferase, Cellular Activity, and Anticancer Activity in Mice

McNamara, Dennis J.; Dobrusin, Ellen M.; Leonard, Daniele; Shuler, Kevon R.; Kaltenbronn, James S.; Quin, John; Bur, Scott K.; Thomas, Charles E.; Doherty, Annette M.; Scholten, Jeffrey D.; Zimmerman, Karen K.; Gibbs, Barbara S.; Gowan, Richard; Latash, Michael P.; Leopold, Wilbur R.; Przybranowski, Sally; Sebolt–Leopold, Judith S.

doi:10.1021/jm970470c

Cited by 26 publications

(14 citation statements)

References 11 publications

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“…Several substitutions to the initial lead structure were tested with moderate success. However, the resulting cellular activity was in general very low, presumably due to permeability difficulties [183].…”

Section: Library Compoundsmentioning

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: Library Compoundsmentioning

confidence: 99%

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

Sousa

Fernandes²,

Ramos³

2008

CMC

108

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“…This reaction is catalyzed by the enzyme protein farnesyltransferase (FTase). Inhibition of this enzyme has been shown to reduce Ras function both in vitro and in vivo. − Therefore, the inhibition of FTase represents an intriguing target for cancer chemotherapy. , …”

Section: Introductionmentioning

confidence: 99%

Second-Generation Peptidomimetic Inhibitors of Protein Farnesyltransferase Demonstrating Improved Cellular Potency and Significant in Vivo Efficacy

et al. 1999

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The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.

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“…9 To circumvent this problem, a number of groups have prepared peptidomimetics and pseudo-peptides as FPT inhibitors and some of these compounds have shown promising results in cellular and in vivo activity. 10 We have previously reported SCH 44342, a nonpeptidic tricyclic compound with FPT and COS activities of 0.25 and 1 µM, respectively. 11 Although this compound did not show any in vivo efficacy, its C-11 saturated analogue, SCH 55495, which was equipotent in FPT activity, demonstrated moderate in vivo activity in mice model studies (inhibiting 30% of tumor growth in SW-620 at 50 mpk bid).…”

mentioning

confidence: 99%

“…Although some of these inhibitors showed very good in vitro activity, they were found to be inactive in the whole cells and in vivo studies, possibly due to poor cellular uptake and metabolic instability . To circumvent this problem, a number of groups have prepared peptidomimetics and pseudopeptides as FPT inhibitors and some of these compounds have shown promising results in cellular and in vivo activity …”

mentioning

confidence: 99%

Potent, Selective, and Orally Bioavailable Tricyclic Pyridyl Acetamide N-Oxide Inhibitors of Farnesyl Protein Transferase with Enhanced in Vivo Antitumor Activity

Njoroge¹,

Vibulbhan²,

Pinto³

et al. 1998

J. Med. Chem.

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We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.

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C-Terminal Modifications of Histidyl-N-benzylglycinamides To Give Improved Inhibition of Ras Farnesyltransferase, Cellular Activity, and Anticancer Activity in Mice

Cited by 26 publications

References 11 publications

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

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

Second-Generation Peptidomimetic Inhibitors of Protein Farnesyltransferase Demonstrating Improved Cellular Potency and Significant in Vivo Efficacy

Potent, Selective, and Orally Bioavailable Tricyclic Pyridyl Acetamide N-Oxide Inhibitors of Farnesyl Protein Transferase with Enhanced in Vivo Antitumor Activity

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