17DMAG

17dmag is a water soluble derivate of Geldanamycin

Description
17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG) is the first water-soluble analogue of 17AAG. This Hsp90 inhibitor seems to be good in preclinical studies. [1].

17DMAG has very good bioavailability, is freely distributed to the body tissues, and is metabolized significantly less than is 17AAG[2].

1. Workman P., 2003. Overview: translating Hsp90 biology into Hsp90 drugs. Curr Cancer Drug Targets 3(5):297-300
2. Egorin MJ, et al., 2002. Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol 49(1):7-19

Formula: C₃₂H₄₈N₄O₈, HCl
Molecular weight: 652

Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 [?]* and client proteins in melanoma models.

mith V, Sausville EA, Camalier RF, Fiebig HH, Burger AM
Tumor Biology Center at the University of Freiburg, Breisacherstr. 117, 79106, Freiburg, Germany.

The heat shock protein Hsp90 [?]* is a potential target for drug discovery of novel anticancer agents. By affecting this protein, several cell signaling pathways may be simultaneously modulated. The geldanamycin analog 17AAG has been shown to inhibit Hsp90 [?]* and associated proteins. Its clinical use, however, is hampered by poor solubility and thus, difficulties in formulation. Therefore, a water-soluble derivative was desirable and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) is such a derivative. Studies were carried out in order to evaluate the activity and molecular mechanism(s) of 17DMAG in comparison with those of 17-allylamino-demethoxygeldanamycin (17AAG). 17DMAG was found to be more potent than 17AAG in a panel of 64 different patient-derived tumor explants studied in vitro in the clonogenic assay. The tumor types that responded best included mammary cancers (six of eight), head and neck cancers (two of two), sarcomas (four of four), pancreas carcinoma (two of three), colon tumors (four of eight for 17AAG and six of eight for 17DMAG), and melanoma (two of seven). Bioinformatic comparisons suggested that, while 17AAG and 17DMAG are likely to share the same mode(s) of action, there was very little similarity with standard anticancer agents. Using three permanent human melanoma cell lines with differing sensitivities to 17AAG and 17DMAG (MEXF 276L, MEXF 462NL and MEXF 514L), we found that Hsp90 [?]* protein was reduced following treatment at a concentration associated with total growth inhibition. The latter occurred in MEXF 276L cells only, which are most sensitive to both compounds. The depletion of Hsp90 [?]* was more pronounced in cells exposed to 17DMAG than in those treated with 17AAG. The reduction in Hsp90 [?]* was associated with the expression of erbB2 and erbB3 in MEXF 276L, while erbB2 and erbB3 were absent in the more resistant MEXF 462NL and MEXF 514L cells. Levels of known Hsp90 [?]* client proteins such as phosphorylated AKT followed by AKT, cyclin D1 [?]* preceding cdk4*, and craf-1* declined as a result of drug treatment in all three melanoma cell lines. However, the duration of drug exposure needed to achieve these effects was variable. All cell lines showed increased expression of Hsp70 [?]* and activated cleavage of PARP*. No change in PI3K [?]* expression was observed and all melanoma cells were found to harbor the activating V599E BRAF * kinase mutation. The results of our in vitro studies are consistent with both 17AAG and 17DMAG acting via the same molecular mechanism, i.e. by modulating Hsp90 [?]* function. Since 17DMAG can be formulated in physiological aqueous solutions, the data reported here strongly support the development of 17DMAG as a more pharmaceutically practicable congener of 17AAG.

Int J Cancer. 2006 Nov 9; : 17096329

Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers.

Kunitoshi Tomii , Kazunori Tsukuda , Shinichi Toyooka , Hideaki Dote , Tadashi Hanafusa , Hiroaki Asano , Minoru Naitou , Hiroyoshi Doihara , Takumi Kisimoto , Hideki Katayama , Harvery I Pass , Hiroshi Date , Nobuyoshi Shimizu

Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. (c) 2006 Wiley-Liss, Inc.

Cancer Res. 2006 Sep 15;66 (18):9211-20 16982765

Inhibition of hsp90 compromises the DNA damage response to radiation.

Hideaki Dote , William E Burgan , Kevin Camphausen , Philip J Tofilon
Inhibitors of the molecular chaperone Hsp90 have been shown to enhance tumor cell radiosensitivity. To begin to address the mechanism responsible, we have determined the effect of the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG) on the DNA damage response to radiation. Exposure of MiaPaCa tumor cells to 17DMAG, which results in radiosensitization, inhibited the repair of DNA double-strand breaks according to gammaH2AX foci dispersal and the neutral comet assay. This repair inhibition was associated with reduced DNA-PK catalytic subunit (DNA-PKcs) phosphorylation after irradiation and a disruption of DNA-PKcs/ErbB1 interaction. These data suggest that the previously established 17DMAG-mediated reduction in ErbB1 activity reduces its interaction with DNA-PKcs and thus accounts for the attenuation of radiation-induced DNA-PK activation. 17DMAG was also found to abrogate the activation of the G(2)- and S-phase cell cycle checkpoints. Associated with these events was a reduction in radiation-induced ataxia-telangiectasia mutated (ATM) activation and foci formation in 17DMAG-treated cells. Although no interaction between ATM and Hsp90 was detected, Hsp90 was found to interact with the MRE11/Rad50/NBS1 (MRN) complex. 17DMAG exposure reduced the ability of the MRN components to form nuclear foci after irradiation. Moreover, 17DMAG exposure reduced the interaction between NBS1 and ATM, although no degradation of the MRN complex was detected. These results suggest that the diminished radiation-induced activation of ATM in 17DMAG-treated cells was the result of a compromise in the function of the MRN complex. These data indicate that Hsp90 can contribute to the DNA damage response to radiation affecting both DNA repair and cell cycle checkpoint activation. (Cancer Res 2006; 66(18): 9211-20).

Cancer Res. 2005 Aug 1;65 (15):6967-75 16061682

ErbB3 expression predicts tumor cell radiosensitization induced by Hsp90 inhibition.

Hideaki Dote , David Cerna , William E Burgan , Kevin Camphausen , Philip J Tofilon

The ability to identify tumors that are susceptible to a given molecularly targeted radiosensitizer would be of clinical benefit. Towards this end, we have investigated the effects of a representative Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG), on the radiosensitivity of a panel of human tumor cell lines. 17DMAG was previously shown to enhance the radiosensitivity of a number of human cell lines, which correlated with the loss of ErbB2. We now report on cell lines in which 17DMAG induced the degradation of ErbB2, yet had no effect on radiosensitivity. In a comparison of ErbB family members, ErbB3 protein was only detectable in cells resistant to 17DMAG-induced radiosensitization. To determine whether ErbB3 plays a casual role in this resistance, short interfering RNA (siRNA) was used to knockdown ErbB3 in the resistant cell line AsPC1. Whereas individual treatments with siRNA to ErbB3 or 17DMAG had no effect on radiosensitivity, the combination, which reduced both ErbB2 and ErbB3, resulted in a significant enhancement in AsPC1 radiosensitivity. In contrast to siRNA to ErbB3 or 17DMAG treatments only, AsPC1 cell exposure to the combination also resulted in a decrease in ErbB1 kinase activity. These results indicate that ErbB3 expression predicts for tumor cell susceptibility to and suggests that the loss of ErbB1 signaling activity is necessary for 17DMAG-induced radiosensitization. However, for cell lines sensitized by 17DMAG, treatment with siRNA to ErbB2, which reduced ErbB1 activity, had no effect on radiosensitivity. These results suggest that, whereas the loss of ErbB1 signaling may be necessary for 17DMAG-induced radiosensitization, it is not sufficient.
Mesh-terms: Cell Line, Tumor; HSP90 Heat-Shock Proteins, antagonists & inhibitors; Humans; Male; Pancreatic Neoplasms, enzymology; Pancreatic Neoplasms, metabolism; Pancreatic Neoplasms, radiotherapy; Prostatic Neoplasms, enzymology; Prostatic Neoplasms, metabolism; Prostatic Neoplasms, radiotherapy; Protein-Serine-Threonine Kinases, metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins, metabolism; Quinones, pharmacology; RNA, Small Interfering, genetics; Radiation Tolerance, drug effects; Radiation Tolerance, physiology; Radiation-Sensitizing Agents, pharmacology; Receptor, erbB-2, metabolism; Receptor, erbB-3, antagonists & inhibitors; Receptor, erbB-3, biosynthesis; Receptor, erbB-3, genetics; raf Kinases, metabolism;

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