17-AAG (KOS953)
(Synonyms: 坦螺旋霉素; 17-AAG; NSC 330507; CP 127374) 目录号 : GC11720
17-AAG（格尔德霉素）是一种天然的苯醌安沙霉素抗生素，是第一个确定的 Hsp90 抑制剂。
Cas No.:75747-14-7
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
17-AAG(Geldanamycin), a natural benzoquinone ansamycin antibiotic, is the first established inhibitor of Hsp90. It inhibits Hsp90's ATPase function through binding to its amino-terminal domain[5].
17-AAG as a potent HSP90 inhibitor with an IC50 value of 6 nM in BT474 cells, inhibited the binding of HSP90 to HIF-1α[2]. In a concentration- and time-dependent manner, inhibition of Hsp90 by 17-AAG decreased Akt and eNOS expression. Inhibition of eNOS expression by 17-AAG occurred at the transcriptional level. Furthermore, treatment with 17-AAG decreased basal and vascular endothelial growth factor-stimulated Akt and eNOS phosphorylation. This corresponded with decreased NO production and inhibition of endothelial cell migration and angiogenesis[3].17AAG topically applied to mouse skin, inhibits UVR-induced development of cutaneous squamous cell carcinoma (SCC) [7].
Therapeutic potential of 17-AAG was investigated using nude mice intraperitoneal xenograft. A combination of 17-AAG and DDP could inhibit tumor growth more efficiently, The survival time of the mice was significantly prolonged, supporting the notion that 17-AAG combined with DDP could prolong the survival time of mice[1].17-AAG is able to inhibit the growth of both human glioma cell lines and glioma stem cells in vitro . In addition, 17-AAG can inhibit the growth of intracranial tumors and can synergize with radiation both in tissue culture and in intracranial tumors. This compound was not found to synergize with temozolomide in any of our models of gliomas[6].17-AAG plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth[4].
References:
[1]: Wang Y, Chen Q, et,al. Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells. Cell Death Dis. 2021 Aug 12;12(8):786. doi: 10.1038/s41419-021-04074-z. PMID: 34381017; PMCID: PMC8358027.
[2]: Kamal A, Thao L, et,al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003 Sep 25;425(6956):407-10. doi: 10.1038/nature01913. PMID: 14508491.
[3]: Sun J, Liao JK. Induction of angiogenesis by heat shock protein 90 mediated by protein kinase Akt and endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2238-44. doi: 10.1161/01.ATV.0000147894.22300.4c. Epub 2004 Oct 14. PMID: 15486309; PMCID: PMC2633590.
[4]: Modi S, Stopeck AT, et,al. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin Oncol. 2007 Dec 1;25(34):5410-7. doi: 10.1200/JCO.2007.11.7960. PMID: 18048823.
[5]: Neckers L, Schulte TW, et,al. Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs. 1999;17(4):361-73. doi: 10.1023/a:1006382320697. PMID: 10759403.
[6]: Sauvageot CM, Weatherbee JL, et,al. Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol. 2009 Apr;11(2):109-21. doi: 10.1215/15228517-2008-060. Epub 2008 Aug 5. PMID: 18682579; PMCID: PMC2718982.
[7]: Singh A, Singh A, et,al. Topically applied Hsp90 inhibitor 17AAG inhibits UVR-induced cutaneous squamous cell carcinomas. J Invest Dermatol. 2015 Apr;135(4):1098-1107. doi: 10.1038/jid.2014.460. Epub 2014 Oct 22. PMID: 25337691; PMCID: PMC4366283.
17-AAG（格尔德霉素）是一种天然的苯醌安沙霉素抗生素,是第一个确定的 Hsp90 抑制剂。它通过与其氨基末端结构域结合来抑制 Hsp90 的 ATPase 功能[5]。
17-AAG 作为一种有效的 HSP90 抑制剂,在 BT474 细胞中的 IC50 值为 6 nM,可抑制 HSP90 与 HIF-1α[2] 的结合。以浓度和时间依赖性方式,17-AAG 对 Hsp90 的抑制作用降低了 Akt 和 eNOS 的表达。 17-AAG 对 eNOS 表达的抑制发生在转录水平。此外,用 17-AAG 治疗可降低基础和血管内皮生长因子刺激的 Akt 和 eNOS 磷酸化。这对应于 NO 生成减少以及内皮细胞迁移和血管生成的抑制[3]。17AAG 局部应用于小鼠皮肤,抑制 UVR 诱导的皮肤鳞状细胞癌 (SCC) 的发展[7 ].
使用裸鼠腹膜内异种移植物研究了 17-AAG 的治疗潜力。 17-AAG与DDP联用可更有效地抑制肿瘤生长,小鼠的生存时间明显延长,支持17-AAG与DDP联用可延长小鼠生存时间的观点[1].17-AAG 能够在体外抑制人神经胶质瘤细胞系和神经胶质瘤干细胞的生长。此外,17-AAG 可抑制颅内肿瘤的生长,并可在组织培养和颅内肿瘤中与放疗协同作用。在我们的任何神经胶质瘤模型中均未发现该化合物与替莫唑胺有协同作用[6]。17-AAG 加曲妥珠单抗耐受性良好,在 HER-2 患者中具有抗肿瘤活性+ 曲妥珠单抗治疗期间肿瘤进展的乳腺癌。这些数据表明,Hsp90 功能可在体内被抑制到足以抑制肿瘤生长的程度[4]。
| Cell experiment [1]: | |
|
Cell lines |
HO-8910 cells |
|
Preparation Method |
HO-8910 cells were treated with different concentrations of Hsp90 inhibitor 17-AAG, and cells treated without 17-AAG were regarded as the control group. |
|
Reaction Conditions |
17-AAG 0.25、0.5 and 5 μM for 4, 8, 12, and 24 h |
|
Applications |
The levels of Rad50 and Ku80 decreased after 8 h in cells treated with relative low concentration of 17-AAG (0.5 μM). In the groups treated with relative high concentration of 17-AAG (5 μM), Rad50 significantly decreased after 4 h, and Ku80 also decreased after 8 h, indicating that DSBs repair proteins were downregulated in a dose and time-depend manner and Hsp90 inhibition could affect DSBs repair. |
| Animal experiment [2]: | |
|
Animal models |
Female 4–5weeks old, 18–20 g BALB/c nude mice |
|
Preparation Method |
The mice were randomly assigned to three groups (n = 4/group). The luciferase-expressing HO-8910 cells were injected intraperitoneally into groups. After two weeks, mice were intraperitoneally injected with DDP, DDP combined with 17-AAG (50 mg/kg),once a week for up to 6 weeks. |
|
Dosage form |
50 mg/kg, once a week for up to 6 weeks |
|
Applications |
A combination of 17-AAG and DDP could inhibit tumor growth more efficiently, The survival time of the mice was significantly prolonged, supporting the notion that 17-AAG combined with DDP could prolong the survival time of mice. |
|
References: [1]. Wang Y, Chen Q, et,al. Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells. Cell Death Dis. 2021 Aug 12;12(8):786. doi: 10.1038/s41419-021-04074-z. PMID: 34381017; PMCID: PMC8358027. |
|
| Cas No. | 75747-14-7 | SDF | |
| 别名 | 坦螺旋霉素; 17-AAG; NSC 330507; CP 127374 | ||
| 化学名 | [(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-21-(prop-2-enylamino)-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate | ||
| Canonical SMILES | CC1CC(C(C(C=C(C(C(C=CC=C(C(=O)NC2=CC(=O)C(=C(C1)C2=O)NCC=C)C)OC)OC(=O)N)C)C)O)OC | ||
| 分子式 | C31H43N3O8 | 分子量 | 585.7 |
| 溶解度 | ≥ 24.95 mg/mL in DMSO, ≥ 9.56 mg/mL in EtOH with ultrasonic | 储存条件 | 4°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.7074 mL | 8.5368 mL | 17.0736 mL |
| 5 mM | 0.3415 mL | 1.7074 mL | 3.4147 mL |
| 10 mM | 0.1707 mL | 0.8537 mL | 1.7074 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet