Oreganic Acid, a Potent Inhibitor of Ras Farnesyl-Protein Transferase

Silverman, Keith C.; Jayasuriya, Hiranthi; Cascales, Carmen; Vilella, Dolores; Bills, Gerald F.; Jenkins, Rosalind G.; Singh, Sheo B.; Lingham, Russell B.

doi:10.1006/bbrc.1997.6314

Cited by 14 publications

(10 citation statements)

References 24 publications

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“…41,42 Additionally, a number of microbially derived inhibitors that resemble FPP in structure and are competitive with FPP in the farnesylation reaction have been isolated. [43][44][45][46][47][48][49][50][51][52] Surprisingly, several peptide-based inhibitors that compete with FPP have also been described 53,54 (for example, PD 083176; FIG. 1).…”

Section: Development Of Fptase Inhibitorsmentioning

confidence: 99%

Farnesyltransferase Inhibitors: Preclinical Development

Kohl

1999

Annals of the New York Academy of Sciences

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The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization, farnesyl-protein transferase (FPTase), would be a target for the development of novel anticancer agents. We have developed potent, cell-active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras-induced transformation of mammalian cells in monolayer cultures. In vivo, these compounds block the growth of ras-transformed fibroblasts in a nude mouse xenograft model and block the growth and, in some cases, cause regression of mammary and salivary tumors in several strains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers, a hypothesis that is currently being tested in the clinic.

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Section: Development Of Fptase Inhibitorsmentioning

confidence: 99%

Farnesyltransferase Inhibitors: Preclinical Development

Kohl

1999

Annals of the New York Academy of Sciences

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“…In last few years we have reported the isolation of selective novel FPTase inhibitors from microbial sources. These include chaetomellic acids, actinoplanic acids, preussomerins, cylindrols, barceloneic acid, fusidienol, and oreganic acid . Other inhibitors have been reported by several groups and include pepticinnamins, gliotoxin, 10‘-desmethoxystreptonigrin, and manumycin analogs .…”

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confidence: 99%

Fusidienol A: A Novel Ras Farnesyl-Protein Transferase Inhibitor from Phoma sp.

et al. 1997

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“…Furthermore, clavaric acid inhibited rat liver squalene synthase with an IC 50 value of 250 μM, reinforcing the conclusion that clavaric acid is a specific inhibitor of FPTase. Chaetomellic acid A and oreganic acid, compounds that are competitive with FPP, ,, when tested using either peptide substrate, inhibited FPTase activity with similar IC 50 values. These compounds are also very poor inhibitors of human GGPTase-I.…”

Section: Resultsmentioning

confidence: 98%

“…To identify unique chemical templates on which to design inhibitors of FPTase, we initiated a program to identify inhibitors of FPTase from natural product sources. We discovered chaetomellic acids, ,, fusidienol A, preussomerins and deoxypreussomerins, actinoplanic acids, − barceloneic acid, cylindrols, and oreganic acid, , which are structurally diverse, selective, and potent natural product inhibitors of FPTase. Three of these inhibitors (chaetomellic acids, actinoplanic acids, and oreganic acid) were competitive with the farnesyl diphosphate substrate, while the remainder were noncompetitive with either substrate.…”

Section: Introductionmentioning

confidence: 99%

Clavaric Acid and Steroidal Analogues as Ras- and FPP-Directed Inhibitors of Human Farnesyl-Protein Transferase

Rb¹,

Kc²,

Jayasuriya³

et al. 1998

J. Med. Chem.

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We have identified a novel fungal metabolite that is an inhibitor of human farnesyl-protein transferase (FPTase) by randomly screening natural product extracts using a high-throughput biochemical assay. Clavaric acid [24, 25-dihydroxy-2-(3-hydroxy-3-methylglutaryl)lanostan-3-one] was isolated from Clavariadelphus truncatus; it specifically inhibits human FPTase (IC50 = 1.3 microM) and does not inhibit geranylgeranyl-protein transferase-I (GGPTase-I) or squalene synthase activity. It is competitive with respect to Ras and is a reversible inhibitor of FPTase. An alkaline hydrolysis product of clavaric acid, clavarinone [2,24,25-trihydroxylanostan-3-one], lacking the 3-hydroxy-3-methylglutaric acid side chain is less active as a FPTase inhibitor. Similarly, a methyl ester derivative of clavaric acid is also inactive. In Rat1 ras-transformed cells clavaric acid and lovastatin inhibited Ras processing without being overtly cytotoxic. Excess mevalonate reversed the effects of lovastatin but not of clavaric acid suggesting that the block on Ras processing by clavaric acid was due to inhibition of FPTase and not due to inhibition of HMG-CoA reductase. Despite these results, the possibility existed that clavaric acid inhibited Ras processing by directly inhibiting HMG-CoA reductase. To directly examine the effects of clavaric acid and clavarinone on HMG-CoA reductase, cholesterol synthesis was measured in HepG2 cells. No inhibition of HMG-CoA reductase was observed indicating that the inhibition of Ras processing by this class of compounds is due to inhibition of FPTase. To date, clavaric acid is the second reported nitrogen-free compound that competes with Ras to inhibit FPTase activity. A series of related compounds derived from computer-based similarity searches and subsequent rational chemical synthetic design provided compounds that exhibited a range of activity (0.04 --> 100 microM) against FPTase. Modest changes in the structures of these inhibitors dramatically change the inhibitory activity of these inhibitors.

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Oreganic Acid, a Potent Inhibitor of Ras Farnesyl-Protein Transferase

Cited by 14 publications

References 24 publications

Farnesyltransferase Inhibitors: Preclinical Development

Farnesyltransferase Inhibitors: Preclinical Development

Fusidienol A: A Novel Ras Farnesyl-Protein Transferase Inhibitor from Phoma sp.

Clavaric Acid and Steroidal Analogues as Ras- and FPP-Directed Inhibitors of Human Farnesyl-Protein Transferase

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