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17-DMAG (Alvespimycin) HCl

カタログ番号GC13044

17-DMAG (アルベスピマイシン) HCl (17-DMAG 塩酸塩; KOS-1022; BMS 826476) は Hsp90 の強力な阻害剤であり、62±29 nM の EC50 で Hsp90 に結合します。

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17-DMAG (Alvespimycin) HCl 化学構造

Cas No.: 467214-21-7

サイズ 価格 在庫数 個数
10mM (in 1mL DMSO)
$69.00
在庫あり
200mg
$378.00
在庫あり

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

View current batch:

Protocol

Kinase experiment [1]:

Fluorescence polarization (FP)-based competition binding assay

This assay utilized a boron difluoride dipyrromethene (BODIPY) labeled geldanamycin analogue (BODIPY-AG) as a probe and measured fluorescence polarization upon binding of the probe to a protein. Native human Hsp90 protein (α + β isoforms) is isolated from HeLa cells. BODIPY-AG solution was freshly prepared in FP assay buffer (20 mM HEPES-KOH, pH 7.3, 1.0 mM EDTA, 100 mM KCl, 5.0 mM MgCl2, 0.01% NP-40, 0.1 mg/mL fresh bovine γ-globulin (BGG), 1.0 mM fresh DTT, and protease inhibitor from stock solution in DMSO). Competition curves were obtained by mixing 10 μL each of a solution containing BODIPY-AG and Hsp90, and a serial dilution of 17-DMAG freshly prepared in FP assay buffer from stock solution in DMSO. Final concentrations were 10 nM BODIPY-AG, 40 or 60 nM Hsp90, varying concentration of 17-DMAG (0.10 nM ~ 10 μM), and ≤ 0.25% DMSO in a 384-well microplate. After 3-hr incubation at 30°C, fluorescence anisotropy (γEx = 485 nm, γEm = 535 nm) was measured on an EnVision 2100 multilabel plate reader. The IC50 value of 17-DMAG was obtained from the competition curves.

Cell experiment [2]:

Cell lines

Chronic lymphocytic leukemia (CLL)

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

~ 1 μM; 24 or 48 hrs

Applications

In CLL cells, 17-DMAG effectively led to depletion of the Hsp90 client protein, decreasing NF-κB p50/p65 DNA binding, NF-κB target gene transcription and caspase-dependent apoptosis. By targeting the NF-κB family, 17-DMAG selectively mediated cytotoxicity against CLL cells (in dose- and time-dependent manner), but not normal T cells or NK cells important for immune surveillance.

Animal experiment [2]:

Animal models

SCID mice engrafted with TCL1 leukemia cells

Dosage form

10 mg/kg; i.p.; 5 times per week for 16 days

Applications

In a TCL1-SCID transplant mouse model, the 17-DMAG treatment (10 mg/kg) significantly decreased the white blood cell count and prolonged the survival.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Jie Ge, Emmanuel Normant, James R. Porter, Janid A. Ali, Marlene S. Dembski, Yun Gao, Asimina T. Georges, Louis Grenier, Roger H. Pak, Jon Patterson, Jens R. Sydor, Thomas T. Tibbitts, Jeffrey K. Tong, Julian Adams, and Vito J. Palombella. Design, synthesis and biological evaluation of Hydroquinone derivatives of 17-Amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J. Med. Chem. 2006, 49, 4606-4615.

[2]. Hertlein E, Wagner AJ, Jones J, Lin TS, Maddocks KJ, Towns WH 3rd, Goettl VM, Zhang X, Jarjoura D, Raymond CA, West DA, Croce CM, Byrd JC, Johnson AJ. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood. 2010 Jul 8;116(1):45-53.

Background

17-DMAG is an inhibitor of Hsp90 with IC50 value of 62±29nM [1].

17-DMAG can bind to the ATP-binding motif of Hsp90 and inhibit the protein chaperoning activity of Hsp90. It will cause misfolding and subsequent degradation of Hsp90’s client proteins, such as EGFR, AKT, mutant p53, and IKK. Since there is more specific conformation Hsp90 required for 17-DMAG binding in tumor cells and many client proteins of Hsp90 contribute to tumor cell growth, 17-DMAG is usually more toxic to tumor cells than to normal cells [2].

17-DMAG is reported as an antitumor agent with more broadly exploitable activity and more pharmaceutically tractable characteristics in the in vitro and initial in vivo assay. 17-DMAG can effect cell growth when treating the NCI 60 cell lines with it, the mean GI50 is 0.053mM. The in vivo activity of 17-DMAG is tested in four melanoma models using the Freiburg human tumor xenograft panel and two lung xenografts. It shows that 17-DMAG has high activity in the two lung xenografts and two of the four melanoma models, but not in another two, MEXF 462 and MEXF 514 [3].

Reference:
[1] Jie Ge, Emmanuel Normant, James R.  Porter, Janid A. Ali, Marlene S. Dembski, Yun Gao, Asimina T. Georges, Louis Grenier, Roger H. Pak, Jon Patterson, Jens R. Sydor, Thomas T. Tibbitts, Jeffrey K. Tong, Julian Adams, and Vito J. Palombella. Design, synthesis and biological evaluation of Hydroquinone derivatives of 17-Amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J. Med. Chem. 2006, 49, 4606-4615.
[2] Xiaoping Sun, Jillian A.  Bristol, Satoko Iwahori, Stacy R. Hagemeier, Qiao Meng, Elizabeth A. Barlow, Joyce D. Fingeroth, Vera L. Tarakanova, Robert F. Kalejta, Shannon C. Kenney. Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in
Epstein-Barr Virus-Infected Cells.  Journal of Virology. 2013, 87 (18): 10126–10138.
[3] Melinda Hollingshead, Michael Alley, Angelika M.  Burger, Suzanne Borgel,
Christine Pacula-Cox, Heinz-Herbert Fiebig, Edward A.  Sausville. In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol. 2005, 56: 115–125.

Chemical Properties

Cas No. 467214-21-7 SDF
Chemical Name [(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-21-[2-(dimethylamino)ethylamino]-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate;hydrochloride
Canonical SMILES CC1CC(C(C(C=C(C(C(C=CC=C(C(=O)NC2=CC(=O)C(=C(C1)C2=O)NCCN(C)C)C)OC)OC(=O)N)C)C)O)OC.Cl
Formula C32H48N4O8.HCl M.Wt 653.21
溶解度 ≥ 26.2mg/mL in DMSO Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

Prepare stock solution
1 mg 5 mg 10 mg
1 mM 1.5309 mL 7.6545 mL 15.309 mL
5 mM 0.3062 mL 1.5309 mL 3.0618 mL
10 mM 0.1531 mL 0.7655 mL 1.5309 mL
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計算

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
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Review for 17-DMAG (Alvespimycin) HCl

Average Rating: 5 ★★★★★ (Based on Reviews and 7 reference(s) in Google Scholar.)

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