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17-DMAG (Alvespimycin) HCl

现货
Catalog No.
A2213
Hsp90抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 700.00
现货
10mg
¥ 500.00
现货
25mg
¥ 1,000.00
现货
100mg
¥ 2,500.00
现货

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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.

文献引用

1. Katayama K, Noguchi K, et al. "Heat shock protein 90 inhibitors overcome the resistance to Fms-like tyrosine kinase 3 inhibitors in acute myeloid leukemia." Oncotarget. 2018 Sep 28;9(76):34240-34258. PMID:30344940

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt653.21
Cas No.467214-21-7
FormulaC32H48N4O8.HCl
Solubility≥26.2mg/mL in DMSO
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
SDFDownload SDF
Canonical SMILESCC1CC(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
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

荧光偏振(FP)为基础的竞争性结合实验

实验采用氟化硼亚甲基二吡咯(BODIPY)标记的Geldanamycin类似物(BODIPY-AG)作为探针,根据探针与蛋白结合情况,测定荧光偏振。从HeLa细胞中分离活性人类Hsp90蛋白(α + β亚型)。以FP测定缓冲液(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新鲜牛γ-球蛋白(BGG),1.0 mM新鲜DTT以及溶于DMSO的蛋白酶抑制剂)新鲜制备BODIPY-AG溶液。将含BODIPY-AG和Hsp90的溶液(每组10 μL)与连续稀释的17-DMAG(使用FP测定缓冲液新鲜制备)混合,获得竞争性曲线。在384孔板中,各终浓度为10 nM BODIPY-AG,40或60 nM Hsp90,不同浓度的17-DMAG(0.10 nM ~ 10 μM)和≤ 0.25% DMSO。于30°C温育3小时后,使用EnVision 2100多标记酶标仪测定荧光各向异性(γEx = 485 nm,γEm = 535 nm)。由竞争曲线得出17-DMAG的IC50值。

细胞实验 [2]:

细胞系

慢性淋巴细胞白血病(CLL)

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

~ 1 μM;24或48小时

实验结果

在CLL细胞中,17-DMAG有效耗竭Hsp90客户蛋白,从而减少NF-κB p50/p65 DNA结合、NF-κB 靶基因转录以及caspase依赖性凋亡。通过靶向作用于NF-κB家族,17-DMAG选择性地作用于CLL细胞(呈剂量和时间依赖性),而不影响正常T细胞或NK细胞(在免疫监视中发挥重要作用)。

动物实验 [2]:

动物模型

移植TCL1白血病细胞的SCID小鼠

给药剂量

10 mg/kg;腹腔注射;每周5次,持续16天

实验结果

在TCL1-SCID移植小鼠模型中,给予17-DMAG(10 mg/kg)显著降低白细胞数,并延长生存期。

其他注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

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.

生物活性

描述 17-DMAG是Hsp90的抑制剂,IC50值为62±29 nM。
靶点 Hsp90          
IC50 62±29 nM          

质量控制

质量控制和MSDS

批次:

化学结构

17-DMAG (Alvespimycin) HCl

相关生物数据

17-DMAG (Alvespimycin) HCl