Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent

Supko, Jeffrey G.; Hickman, Robert L.; Grever, Michael R.; Malspeis, Louis

doi:10.1007/bf00689048

Cited by 483 publications

(309 citation statements)

References 24 publications

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“…We selected 17-DMAG over GA as our in vivo inhibitor based on published results showing reduced hepatotoxicity in vivo when compared to GA or 17-allylamino-17-demethoxygeldanamycin (17-AAG). 16,18,53,54 Dosages were selected based on studies showing effective treatment and minimal toxicity at dosages under 15 mg/kg administered 3 days per week for 3 weeks. 55 We injected MRL/lpr mice with 17-DMAG 3 days a week on alternating days for 6 weeks, (a) Linear regression of grouped proteinuria scores showed control mice exhibited increased proteinuria, while mice treated with 17-DMAG did not increase in proteinuria.…”

Section: Hsp90 Inhibition Reduced Inflammatory Mediator Production Inmentioning

confidence: 99%

“…15 Unfortunately, GA has low systemic duration (3-4 h) and causes acute hepatic necrosis when administered in vivo. 16 However, the GA derivative 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) exhibits similar effectiveness at inhibiting HSP90 with significantly reduced hepatotoxicity, increased systemic duration (more than 24 h) and greater water solubility. [17][18][19] GA has been shown to reduce the inflammatory response in a murine sepsis model.…”

Section: Introductionmentioning

confidence: 99%

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Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

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Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

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Section: Hsp90 Inhibition Reduced Inflammatory Mediator Production Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

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“…The therapeutic selectivity of HSP90 inhibitors in tumor versus normal cells was explained by increased HSP90 expression and the concomitant formation of a supersensitive multichaperone complex in cancer cells. 154 Due to severe hepatotoxicity in animal studies GA was not further clinically evaluated, 155 whereas 17-AAG (17-allylamino-17-demethoxygeldanamycin), a GA derivate with a significantly reduced toxicity, entered several Phase I and now also Phase II clinical trials with encouraging results. 156 Interestingly, it was shown recently that wild-type and mutant B-RAF proteins are also HSP90 client proteins and are targeted to ubiquitin-dependent proteolysis by 17-AAG.…”

Section: Raf Kinases and Cancer Drug Discoverymentioning

confidence: 99%

Raf kinases: Oncogenesis and drug discovery

Schreck

Rapp

2006

Intl Journal of Cancer

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Raf kinase signaling has been thoroughly investigated over the last 20 years. A-Raf, B-Raf and C-Raf, the 3 mammalian members of the Raf family, are involved in a variety of cellular processes such as growth, proliferation, survival, differentiation and transformation. The detection of B-RAF mutations in a wide variety of human cancers, the description of wildtype and mutant B-RAF as tumor antigens in melanoma and the promising outcome of clinical trials evaluating the Raf inhibitor Nexavar 1 (Sorafenib, BAY 43-9006) have sparked a broad interest in the scientific community. After a short historical detour and an introduction into Raf kinase signaling, we are going to discuss here recent outcomes of Raf kinase research with respect to tumor formation and give an overview on current efforts to develop anticancer therapies interfering with aberrant Raf kinase signaling. ' 2006 Wiley-Liss, Inc.Key words: cancer; clinical trials; transformation; drug delivery; signal transduction; mitogenic cascade; Raf kinases Raf kinases: The historyIn 1983, the cloning of the acutely transforming replication-defective mouse type C virus 3611-MSV and characterization of its acquired oncogene was reported. 1 Since 3611-MSV induces rapidly growing f ibrosarcoma in mice, the transduced oncogene was called v-raf, whereas its cellular homologue was named c-raf. 1 Shortly thereafter, Bister and coworkers described the cloning of the avian acute leukemia retrovirus Mil Hill No. 2 (MH2). 2 MH2 was found to carry a second potential oncogene in addition to vmyc, which was termed v-mil, whereas its cellular counterpart was called c-mil. 3 Already a hybridization analysis and the gross comparison of restriction maps of v-raf and v-mil pointed at sequence homologies between these 2 genes. 4 By direct sequencing of both genes it was finally proven that 3611-MSV and MH2 have integrated orthologues of the same gene into their genomes. 5 In the following we are going to use the nomenclature for Raf kinases as proposed in a recent review from Wellbrock et al. 6 In contrast to all other oncogene kinases known at that time, no tyrosine kinase activity was detected in C-Raf. 7 Indeed, it was found that C-Raf is a serine/threonine kinase. 8,9 This and the observation that Raf coexists with the Myc oncogene in retroviruses 10 led to two novel concepts: (i) There is a tyrosine to serine phosphorylation switch as the growth factor signal enters the cell, and (ii) the mechanistic basis for cooperation between nuclear and cytoplasmic oncogenes as well as for signal transduction from cell surface receptors to the nucleus is the phosphorylation of transcription factor class oncogenes such as Myc. 11-13 Growth factor abrogation and oncogene cooperation studies were performed to corroborate this signaling scheme. 14-17 Additional important early findings were (i) the cooperation between Raf and Myc in growth factor independent proliferation, immortalization and tumor induction, 14,18,19 leading to the Raf-Myc balance model, 20 and (ii) the cell lineage-switch ...

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“…Several natural products act as potent HSP90 inhibitors (e.g., geldanamycin and radicicol; Fig. 1) but exhibited in vivo toxicity and/or stability issues (12,13), restricting their suitability for clinical development. The less toxic geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG; Fig.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Sharp

Prodromou

Boxall

et al. 2007

Molecular Cancer Therapeutics

139

103

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Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K d ) of VER-50589 was 4.5 F 2.2 nmol/L compared with 78.0 F 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC 50 of 21 F 4 nmol/L for VER-50589 compared with 47 F 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI 50 values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 F 15 and 685 F 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and Pglycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI 50 for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as

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Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent

Cited by 483 publications

References 24 publications

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Raf kinases: Oncogenesis and drug discovery

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

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