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Chemical Compound Review:

DMAG [ (3S,5S,6R,7S,8E,10R,11S,12Z,14 E)-21-(2...

Synonyms: alvespimycin, AC1NRBWB, CHEMBL383824, KOS-1022, SureCN5449716, ...

Kaur, G. et al., Bull, E.E. et al., Moreno-Farre, J. et al., Jez, J.M. et al., Castro, J.E. et al., et al.

Castro, Prada, Loria, Kamal, Chen, Burrows, Kipps, Glaze, Lambert, Smith, Page, Johnson, McCormick, Brown, Levine, Covey, Egorin, Eiseman, Holleran, Sausville, Tomaszewski,

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Disease relevance of KOS

The present results are from preclinical toxicity studies evaluating 17-DMAG in rats and dogs [1].

High impact information on KOS

Additionally, ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-AAG or 17-DMAG, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL [2].
In vitro, the activity of 17-DMAG on endothelial cells (human umbilical vein endothelial cells; HUVEC) was tested in FGF-2; and vascular endothelial growth factor (VEGF)-induced proliferation and apoptosis, motility, and extracellular matrix invasion; and on the alignment of capillary like structures in Matrigel [3].
CONCLUSIONS: We show that the Hsp90 targeting agents 17-DMAG and 17-AAG inhibit angiogenesis [3].
17-DMAG consistently increased the expression of Hsp70 [3].
EXPERIMENTAL DESIGN: The effect of 17-DMAG on the levels of three proteins (Raf-1, ErbB2, and Akt) previously implicated in the regulation of radiosensitivity was determined in three human solid tumor cell lines [4].

Biological context of KOS

The oral bioavailability of 17-DMAG might be of advantage in investigating the potential of this compound in clinical trials with antiangiogenic as well as antiproliferative endpoints [3].
17-DMAG treatment also inhibited FGF-2 and VEGF-induced HUVEC proliferation and resulted in apoptosis [3].
A clonogenic assay was then used to evaluate cell survival after exposure to 17-DMAG followed by irradiation [4].
This sensitization seemed to be the result of a 17-DMAG-mediated abrogation of the G(2)- and S-phase cell cycle checkpoints [4].
The method was successfully applied to examine the pharmacokinetics of 17-DMAG in a cancer patient [5].

Anatomical context of KOS

Corresponding concentrations of 17-DMAG enhanced the radiosensitivity of each of the tumor cell lines [4].
The strong effects on endothelial cell functions, in vitro, indicate that the antiangiogenic activity of 17-DMAG/17-AAG could also be due to a direct effect on endothelial cells [3].

Associations of KOS with other chemical compounds

An accurate, sensitive, robust and selective liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin hydrochloride (17-DMAG) in human plasma has been developed and validated [6].

Gene context of KOS

Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90 [7].
Therefore, we have investigated the effects of the orally bioavailable Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) on the radiosensitivity of human tumor cells in vitro and grown as tumor xenografts [4].
We describe the 1.75 A resolution crystal structure of human Hsp90 alpha (residues 9-236) complexed with 17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin (17-DMAG) [7].
For mechanistic insight, the G(2)- and S-phase checkpoints were evaluated in 17-DMAG-treated cells [4].
EXPERIMENTAL DESIGN: The activity of 17-DMAG, in vivo, was evaluated for inhibition of fibroblast growth factor (FGF)-2-induced angiogenesis in s.c. implanted Matrigel in mice [3].

Analytical, diagnostic and therapeutic context of KOS

Finally, the effect of in vivo administration of 17-DMAG in combination with radiation on the growth rate of xenograft tumors was determined [4].
RESULTS: Daily oral administration of 17-DMAG affected the angiogenic response in Matrigel in a dose-dependent manner [3].
Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma [6].
Tissue and plasma 17-DMAG concentrations were measured by HPLC/MS at selected time-points on days 1 and 5 [1].
By immunohistochemistry, 17-DMAG significantly reduced vessel area and numbers of proliferating tumor cells in sections [8].

References

Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance. Glaze, E.R., Lambert, A.L., Smith, A.C., Page, J.G., Johnson, W.D., McCormick, D.L., Brown, A.P., Levine, B.S., Covey, J.M., Egorin, M.J., Eiseman, J.L., Holleran, J.L., Sausville, E.A., Tomaszewski, J.E. Cancer Chemother. Pharmacol. (2005) [Pubmed]
ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Castro, J.E., Prada, C.E., Loria, O., Kamal, A., Chen, L., Burrows, F.J., Kipps, T.J. Blood (2005) [Pubmed]
Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: an orally bioavailable heat shock protein 90 modulator. Kaur, G., Belotti, D., Burger, A.M., Fisher-Nielson, K., Borsotti, P., Riccardi, E., Thillainathan, J., Hollingshead, M., Sausville, E.A., Giavazzi, R. Clin. Cancer Res. (2004) [Pubmed]
Enhanced tumor cell radiosensitivity and abrogation of G2 and S phase arrest by the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin. Bull, E.E., Dote, H., Brady, K.J., Burgan, W.E., Carter, D.J., Cerra, M.A., Oswald, K.A., Hollingshead, M.G., Camphausen, K., Tofilon, P.J. Clin. Cancer Res. (2004) [Pubmed]
Determination of the heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin in plasma by liquid chromatography-electrospray mass spectrometry. Hwang, K., Scripture, C.D., Gutierrez, M., Kummar, S., Figg, W.D., Sparreboom, A. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (2006) [Pubmed]
Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma. Moreno-Farre, J., Asad, Y., Pacey, S., Workman, P., Raynaud, F.I. Rapid Commun. Mass Spectrom. (2006) [Pubmed]
Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Jez, J.M., Chen, J.C., Rastelli, G., Stroud, R.M., Santi, D.V. Chem. Biol. (2003) [Pubmed]
Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. Lang, S.A., Klein, D., Moser, C., Gaumann, A., Glockzin, G., Dahlke, M.H., Dietmaier, W., Bolder, U., Schlitt, H.J., Geissler, E.K., Stoeltzing, O. Mol. Cancer Ther. (2007) [Pubmed]

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