Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives

Schnur, Rodney C.; Corman, Michael L.; Gallaschun, Randall J.; Cooper, Beth; Dee, Michael F.; Doty, Jonathan L.; Muzzi, M. L.; Moyer, James D.; DiOrio, Catherine; Barbacci, Elsa G.

doi:10.1021/jm00019a010

Cited by 192 publications

(120 citation statements)

References 4 publications

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“…In an effort to synthesize water-soluble analogs of 17-AAG, it was recognized that the benzoquinone of 17-AAG could be chemically reduced to its hydroquinone analog. Literature precedence suggested hydroquinone derivatives of geldanamycin were prone to air oxidation and readily converted back to their quinone forms (17,18). However, it was realized that protonation of the aniline nitrogen of 17-AAG hydroquinone decreases electron density in the aromatic ring, thus reducing the oxidative potential of the hydroquinone (Fig.…”

Section: Resultsmentioning

confidence: 99%

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Sydor

Normant

Pien

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

222

160

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Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.T he heat shock response, first identified in 1962 by Ritossa (1), was initially characterized as the induction of select polypeptides in response to an acute cellular heat shock. These polypeptides were proteins that bound to partially unfolded proteins to prevent their aggregation and assist in their refolding (2, 3), and were termed chaperones. Of the heat shock proteins, heat shock protein 90 (Hsp90) in particular has been the subject of intense investigation. Work over the last decade has revealed not only a general protein chaperone role for Hsp90, but also a specific chaperone role in the binding of select conformations or metastable forms of signaling proteins (clients), thereby attenuating their signaling activity (4-6). Client proteins include the targets of key cancer survival and proliferation pathways, including Akt, Bcr-Abl, Her-2, mutant EGFR, and c-Kit, many of which are the subject of individual investigation for points of therapeutic intervention. Therefore, two functions of Hsp90 exist: (i) a general protein chaperone function (protein homeostasis) and (ii) a specific function to modulate the integrity of cell-signaling pathways through the proper folding of pathway members that are Hsp90 clients.Multiple myeloma (MM) is a neoplasm of terminally differentiated B cells (plasma cells) (7). Because of the high protein secr...

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Section: Resultsmentioning

confidence: 99%

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Sydor

Normant

Pien

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

222

160

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“…Geldanamycin has limited clinical potential due to its liver toxicity (Supko et al, 1995). However, the analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG) has reduced liver toxicity but retains the potent antitumour activity of the parent compound (Schulte and Neckers, 1998;Schnur et al, 1995). This derivative has very recently entered phase I clinical trial at our centre and in the USA under the auspices of the US National Cancer Institute and the UK Cancer Research Campaign.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone

et al. 2000

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A number of molecular therapeutic agents, derived from exploiting our knowledge of the oncogenic pathways that are frequently deregulated in cancer, are now entering clinical trials. One of these is the novel agent 17-allylamino-17-demethoxygeldanamycin that acts to inhibit the hsp90 molecular chaperone. Treatment of four human colon cancer cell lines with iso-eective concentrations of this agent resulted in depletion of c-raf-1 and akt and inhibition of signal transduction. We have used gene expression array analysis to identify genes responsive to treatment with this drug. The expression of hsp90 client protein genes was not aected, but hsc hsp70, hsp90b, keratin 8, keratin 18 and caveolin-1 were deregulated following treatment. These observations were consistent with inhibition of signal transduction and suggested a possible mechanism of resistance or recovery from 17-allylamino-17-demethoxygeldanamycin treatment. The results shed light on the molecular mode of action of the hsp90 inhibitors, and suggest possible molecular markers of drug action for use in hypothesis testing clinical trials. Oncogene (2000) 19, 4125 ± 4133.

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“…Some hindered amines could also undergo addition reaction in vitro at C19-of GDM nonenzymatically. 7,8 Several sulfur-containing ansamycins, such as thiazinotrienomycin, trierixin, 3-methylthiorifamycin SV and thiazorifamycins, naphthomycins I and J, and awamycin [23][24][25][26][27][28] had been isolated from Micromonospora sp. or Streptomyces sp.…”

Section: -S-mentioning

confidence: 99%

A pair of sulfur-containing geldanamycin analogs, 19-S-methylgeldanamycin and 4,5-dihydro- 19-S-methylgeldanamycin, from Streptomyces hygroscopicus 17997

Liu

et al. 2011

J Antibiot

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Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives

Cited by 192 publications

References 4 publications

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone

A pair of sulfur-containing geldanamycin analogs, 19-S-methylgeldanamycin and 4,5-dihydro- 19-S-methylgeldanamycin, from Streptomyces hygroscopicus 17997

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