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Chemical Structure| 75747-14-7 Chemical Structure| 75747-14-7

Structure of Tanespimycin
CAS No.: 75747-14-7

Chemical Structure| 75747-14-7

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Tanespimycin (17-AAG) is a potent HSP90 inhibitor with an IC50 of 5 nM, showing a 100-fold higher binding affinity for tumor-derived HSP90 than normal cell-derived HSP90. Tanespimycin depletes cellular STK38/NDR1, reduces STK38 kinase activity, and downregulates the stk38 gene expression.

Synonyms: 17-AAG; NSC 330507; 17-AAG, 17 AAG, 17AAG, BAY 57-9352, BAY 579352, BAY579352, KOS-953, KOS-953, KOS-953, Tanespimycin

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Wnuk, Maciej ; Del Sol-Fernández, Susel ; Błoniarz, Dominika ; Słaby, Julia ; Szmatoła, Tomasz ; Żebrowski, Michał , et al.

Abstract: The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@ CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

Keywords: iron oxide nanoparticles ; CD26 ; HSP90 inhibitor ; drug-induced senescence ; skin cells ; senolysis

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Hu, Lirong ; Fang, Hao ; Abbas, Zaheer ; Luo, Hanpeng ; Brito, Luiz F ; Wang, Yachun , et al.

Abstract: As the stress-inducible isoform of the heat-shock protein 90 (HSP90), the HSP90AA1 gene encodes HSP90α and plays an important role in heat stress (HS) response. Therefore, this study aimed to investigate the role of the HSP90AA1 gene in cellular responses during HS and to identify functional SNPs associated with thermotolerance in Holstein cattle. For the in vitro validation experiment of acute HS, cells from the Madin-Darby bovine kidney cell line were exposed to 42°C for 1 h, and various parameters were assessed, including cell apoptosis, cell autophagy, and the cellular functions of HSP90α by using its inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). Furthermore, the polymorphisms identified in the HSP90AA1 gene and their functions related to HS were validated in vitro. Acute HS exposure induced cell apoptosis, cell autophagy, and upregulated expression of the HSP90AA1 gene. Inhibition of HSP90α by 17-AAG treatment had a significant effect on the expression of the HSP90α protein and increased cell apoptosis. However, autophagy decreased in comparison to the control treatment when cells were exposed to 42°C for 1 h. Five SNPs identified in the HSP90AA1 gene were significantly associated with rectal temperature and respiration score in Holstein cows, in which the rs109256957 SNP is located in the 3′ untranslated region (3′ UTR). Furthermore, we demonstrated that the 3′ UTR of HSP90AA1 is a direct target of bta-miR-1224 by cell transfection with exogenous microRNA (miRNA) mimic and inhibitor. The luciferase assays revealed that the SNP rs109256957 affects the regulation of bta-miR-1224 binding activity and alters the expression of the HSP90AA1 gene. Heat stress–induced HSP90AA1 expression maintains cell survival by inhibiting cell apoptosis and increasing cell autophagy. The rs109256957 located in the 3′ UTR region is a functional variation and it affects the HSP90AA1 expression by altering its binding activity with bta-miR-1224, thereby associating with the physiological parameters of Holstein cows.

Keywords: HSP90AA1 ; heat stress ; cell apoptosis ; cell autophagy ; genetic variation

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Alternative Products

Product Details of Tanespimycin

CAS No. :75747-14-7
Formula : C31H43N3O8
M.W : 585.69
SMILES Code : C=CCNC1=C2C(C(NC(/C(C)=C/C=C\[C@@H]([C@H](/C(C)=C/[C@@H]([C@H]([C@H](C[C@@H](C2)C)OC)O)C)OC(N)=O)OC)=O)=CC1=O)=O
Synonyms :
17-AAG; NSC 330507; 17-AAG, 17 AAG, 17AAG, BAY 57-9352, BAY 579352, BAY579352, KOS-953, KOS-953, KOS-953, Tanespimycin
MDL No. :MFCD04973892

Safety of Tanespimycin

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Related Pathways of Tanespimycin

DNA

Isoform Comparison

Biological Activity

In Vitro:

Cell Line
Concentration Treated Time Description References
Mouse embryonic fibroblasts (MEFs) 0.5 µM 20 hours To study the effect of Hsp90 inhibition on P23H opsin aggregation, results showed that 17-AAG reduced P23H protein aggregation in an HSF-1-dependent mechanism. Hum Mol Genet. 2014 Apr 15;23(8):2164-75
SK-N-SH neuroblastoma cells 1 µM 24 hours To investigate the effect of Hsp90 inhibition on the R135L opsin mutant, results showed that 17-AAG reduced intracellular accumulation of R135L and restored normal opsin localization. Hum Mol Genet. 2014 Apr 15;23(8):2164-75
DU145 human prostate cancer cells 230 nM 72 h To evaluate the growth inhibitory effect of SMA-tanespimycin micelles on DU145 human prostate cancer cells, results showed an IC50 of 230 nM. Int J Pharm. 2011 Nov 25;420(1):111-7.
HeLa cells 500 nM 18 h To study the effect of 17-AAG on Hsp90 conformation, results showed that 17-AAG induced conformational changes in Hsp90, including the closing of the ATP-binding pocket and increased interaction between the NTD and MD. Cell Chem Biol. 2016 Jun 23;23(6):716-26.
HCC827 0.25 µM 72 h To observe the effect of HSP90 inhibitor 17AAG on HCC827 cells, results showed that p53 remained constant in 3D conditions but was activated in 2D conditions. Mol Oncol. 2018 Aug;12(8):1264-1285.
A549 0.25 µM 72 h To observe the effect of HSP90 inhibitor 17AAG on A549 cells, results showed that HSP60 was significantly upregulated in 3D conditions. Mol Oncol. 2018 Aug;12(8):1264-1285.
H441 0.25 µM 72 h To observe the effect of HSP90 inhibitor 17AAG on H441 cells, results showed that p53 was activated in 3D conditions but remained unchanged in 2D conditions. Mol Oncol. 2018 Aug;12(8):1264-1285.
Leishmania mexicana promastigotes 2 μM, 10 μM, 25 μM 2 h To investigate the effects of Hsp90 inhibition on nascent protein synthesis in Leishmania mexicana. The results showed that 25 μM tanespimycin significantly decreased nascent protein synthesis, indicating that Hsp90 inhibition significantly affects protein translation. mSystems. 2021 May 11;6(3):e00089-21.
Leishmania mexicana promastigotes 50 μM 1 h, 4 h To assess the temporal effect of tanespimycin treatment on global protein synthesis in Leishmania mexicana. The results showed that 4 h of Hsp90 inhibition significantly decreased global nascent protein synthesis, indicating that severe Hsp90 inhibition affects protein translation. mSystems. 2021 May 11;6(3):e00089-21.
Z138 cells 0.5 and 1.0 µM 24 h To evaluate the effect of Tanespimycin on Z138 cells, results showed that Tanespimycin significantly inhibited the expression of MYC and CDK9 and induced cell apoptosis. Exp Hematol Oncol. 2024 Feb 7;13(1):14.
HT29 colon adenocarcinoma cells 62.5 nM 8 h To investigate changes in protein complexes following HSP90 inhibition, results showed limited changes in protein complex distribution after HSP90 inhibition. Mol Cell Proteomics. 2023 Feb;22(2):100485.

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Nude mice Subcutaneous DU145 human prostate cancer tumor xenografts Tail vein injection 10 mg/kg Single dose, lasting 23 days To evaluate the anti-cancer efficacy of SMA-tanespimycin micelles in nude mice bearing subcutaneous DU145 human prostate cancer tumor xenografts, results showed significant tumor growth inhibition. Int J Pharm. 2011 Nov 25;420(1):111-7.

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT00779428 Advanced Malignancies PHASE2 COMPLETED 2025-07-13 Dana-Farber Cancer Institute, ... More >>Boston, Massachusetts, 02115, United States Less <<
NCT00773344 Solid Tumors|Breast Cancer PHASE1|PHASE2 COMPLETED 2025-08-09 Premiere Oncology Of Arizona, ... More >>Scottsdale, Arizona, 85260, United States|Arizona Cancer Center, Tucson, Arizona, 85724, United States|Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

1.71mL

0.34mL

0.17mL

8.54mL

1.71mL

0.85mL

17.07mL

3.41mL

1.71mL

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