Potent, non-thiol inhibitors of farnesyltransferase

Breslin, Michael J.; Desolms, S. J.; Giuliani, Elizabeth A.; Stokker, G. E.; Graham, Samuel; Pompliano, David L.; Mosser, Scott D.; Hamilton, Kelly; Hutchinson, John H.

doi:10.1016/s0960-894x(98)00586-1

Cited by 34 publications

(26 citation statements)

References 19 publications

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“…Attention was now directed toward the replacement of the sulfhydryl of the "Cys" residue of the pseudopeptide with a more stable moiety. In a series of N-arylalkylpseudopeptide FTIs [112], the Merck group had found that the sulfhydryl residue could be replaced with imidazole or a variety of aromatic residues [113], paralleling the earlier findings of the Parke-Davis group [114]. A combination of this finding with the L745631 class of compounds has recently led to an exceptionally potent and selective series of FTIs, represented by compound A in Fig.…”

Section: B Natural Products As Ftase Inhibitorsmentioning

confidence: 74%

Non-Peptidic Prenyltransferase Inhibitors: Diverse Structural Classes and Surprising Anti-Cancer Mechanisms

Gibbs

Zahn

Sebolt–Leopold

2001

CMC

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The development of farnesyltransferase inhibitors (FTIs) has been one of the most active areas of anticancer drug development for the past ten years. This review presents a general overview of the developments in this area, along with a critical appraisal of the anticancer activity of FTIs. A historical survey of the protein prenylation field is given, in particular to emphasize the key role played by the Ras oncoprotein in driving the discovery of prenyltransferase enzymes. The different classes of prenylated proteins will be described along with the biochemical characteristics of the key drug target--farnesyltransferase (FTase). Numerous potent farnesyltransferase inhibitors have been developed. The FTIs developed can be separated into three different categories, based on their origin and/or mechanism of action: a) natural products; b) peptidomimetics and other CAAX-competitive inhibitors; c) farnesyl pyrophosphate (FPP) mimetics or analogs and other FPP-competitive inhibitors. Along with a survey of newer FTIs in each class, the development of several representative, potent compounds will be discussed in depth as we discuss the potential advantages and liabilities of each class. Particular emphasis is given to the discovery of new, more potent FPP-competitive FTIs of several diverse structural classes. Testing of different FTIs for their ability to block the growth of various cancer cell types in animal models will be discussed. There are a number of key differences between these compounds and traditional cytotoxic cancer chemotherapeutic agents, with surprising exceptions to their expected modes of action. As some FTIs have entered human clinical trials, answers may soon become available to key mechanistic questions concerning the extent and nature of their antitumor growth properties.

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Section: B Natural Products As Ftase Inhibitorsmentioning

confidence: 74%

Non-Peptidic Prenyltransferase Inhibitors: Diverse Structural Classes and Surprising Anti-Cancer Mechanisms

Gibbs

Zahn

Sebolt–Leopold

2001

CMC

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“…It is not clear why the nitrile functionality should be an exceptional replacement for the relatively lipophilic 7-substituents which we had previously identified to be important for inhibitory potency. However, it is interesting to note that a 4-cyanophenylmethyl substituent in several different series (24,25) has been independently found to provide potent FT inhibitors.…”

Section: Tetrahydrobenzodiazepine Inhibitorsmentioning

confidence: 99%

Farnesyltransferase Inhibitors: From Squalene Synthase Inhibitors to the Clinical Agent BMS-214662

Hunt

2001

Anticancer Agents

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We have discovered a number of distinct classes of inhibitors of the enzyme farnesyltransferase, an attractive new therapeutic target in oncology. The inhibitor classes include ones that are farnesylpyrophosphate-based, bisubstrates, thiol--and imidazole-based tetrapeptides, imidazole-based dipeptides and ultimately imidazole-based tetrahydrobenzodiazepines. The latter class yielded (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H--imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), which has entered clinical trials.

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“…Development is therefore directed towards the so called "non-thiol" farnesyltransferase inhibitors [2][3][4]. We [10,11] and others [12][13][14][15] have shown that the cysteine residue in CAAX-peptidomimetic farnesyltransferase inhibitors can be replaced by aryl moieties, a finding that led to the postulation of two hitherto unknown aryl binding sites in or near the farnesyltransferase's active site [13,14]. Employing flexible docking of several non-thiol farnesyltransferase inhibitors known from literature and some model compounds based on our benzophenone scaffold [16][17][18] as well as performing GRID searches, we have identified two regions in or near farnesyltransferase's active site which we suggest as being the postulated aryl binding sites [10,19].…”

Section: Introductionmentioning

confidence: 99%

Non-Thiol Farnesyltransferase Inhibitors: Evaluation of Different AA(X)-Peptidomimetic Substructures in Combination with Arylic Cysteine Replacements

Sakowski

Böhm

Sattler

et al. 2002

Arch. Pharm. Pharm. Med. Chem.

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Potent, non-thiol inhibitors of farnesyltransferase

Cited by 34 publications

References 19 publications

Non-Peptidic Prenyltransferase Inhibitors: Diverse Structural Classes and Surprising Anti-Cancer Mechanisms

Non-Peptidic Prenyltransferase Inhibitors: Diverse Structural Classes and Surprising Anti-Cancer Mechanisms

Farnesyltransferase Inhibitors: From Squalene Synthase Inhibitors to the Clinical Agent BMS-214662

Non-Thiol Farnesyltransferase Inhibitors: Evaluation of Different AA(X)-Peptidomimetic Substructures in Combination with Arylic Cysteine Replacements

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