AlvespimycinHsp90 inhibitor,potent and selective CAS# 467214-20-6 |
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| Cas No. | 467214-20-6 | SDF | Download SDF |
| PubChem ID | 5288674 | Appearance | Powder |
| Formula | C32H48N4O8 | M.Wt | 616.75 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | 17-DMAG; NSC 707545 | ||
| Solubility | Soluble in Chloroform,Dichloromethane,Ethyl Acetate,DMSO,Acetone,etc. | ||
| Chemical Name | [(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-[2-(dimethylamino)ethylamino]-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl] carbamate | ||
| 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 | ||
| Standard InChIKey | KUFRQPKVAWMTJO-LMZWQJSESA-N | ||
| Standard InChI | InChI=1S/C32H48N4O8/c1-18-14-22-27(34-12-13-36(5)6)24(37)17-23(29(22)39)35-31(40)19(2)10-9-11-25(42-7)30(44-32(33)41)21(4)16-20(3)28(38)26(15-18)43-8/h9-11,16-18,20,25-26,28,30,34,38H,12-15H2,1-8H3,(H2,33,41)(H,35,40)/b11-9-,19-10+,21-16+/t18-,20+,25+,26+,28-,30+/m1/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Alvespimycin is a potent inhibitor of Hsp90, binding to Hsp90 with an EC50 of 62 ± 29 nM.In Vitro:Alvespimycin is a potent inhibitor of Hsp90, binding to Hsp90 with an EC50 of 62 nM. Alvespimycin (17-DMAG) inhibits the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and causes down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition, for Her2 degradation with EC50 of 8 ± 4 nM and 46 ± 24 nM in SKBR3 and SKOV3 cells, respectively; for Hsp70 induction with EC50 of 4 ± 2 nM and 14 ± 7 nM in SKBR3 and SKOV3 cells, respectively[1]. Compared with the vehicle control, Alvespimycin dose-dependent apoptosis (P<0.001 averaged across 24- and 48-hour time points) at concentrations of 50 nM to 500 nM, which represent pharmacologically attainable doses. Similar to many other agents, Alvespimycin also demonstrates time-dependent apoptosis (P <0.001, averaged across all doses) in chronic lymphocytic leukemia (CLL) cells with extended exposure from 24 to 48 hours. In addition, Alvespimycin is much more potent after 24 and 48 hours of treatment than 17-AAG[2].In Vivo:The tumors are grown for two months before the start of i.p. injections every four days over one month with 0, 50, 100 and 200 mg/kg dipalmitoyl-radicicol or 0, 5, 10 and 20 mg/kg Alvespimycin. Despite sample heterogeneity, the HSP90 inhibitor-treated animals have significantly lower tumour volumes than the vehicle control-treated animals. HSP90 inhibitors have been shown to cause liver toxicity in an animal model of gastrointestinal cancer. Nevertheless, the reduction in tumor size using dipalmitoyl-radicicol is statistically significant at 100 mg/kg, while Alvespimycin at either 10 or 20 mg/kg elicits a significant reduction in tumor size[3]. References: | |||||
Alvespimycin Dilution Calculator
Alvespimycin Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.6214 mL | 8.107 mL | 16.214 mL | 32.4281 mL | 40.5351 mL |
| 5 mM | 0.3243 mL | 1.6214 mL | 3.2428 mL | 6.4856 mL | 8.107 mL |
| 10 mM | 0.1621 mL | 0.8107 mL | 1.6214 mL | 3.2428 mL | 4.0535 mL |
| 50 mM | 0.0324 mL | 0.1621 mL | 0.3243 mL | 0.6486 mL | 0.8107 mL |
| 100 mM | 0.0162 mL | 0.0811 mL | 0.1621 mL | 0.3243 mL | 0.4054 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Alvespimycin is a selective Hsp90 inhibitor with a GI50 of 53 nM.
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The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma.[Pubmed:25920748]
Cancer Biol Ther. 2015;16(6):949-57.
The unsatisfactory outcomes for osteosarcoma necessitate novel therapeutic strategies. This study evaluated the effect of the telomerase inhibitor imetelstat in pre-clinical models of human osteosarcoma. Because the chaperone molecule HSP90 facilitates the assembly of telomerase protein, the ability of the HSP90 inhibitor Alvespimycin to potentiate the effect of the telomerase inhibitor was assessed. The effect of single or combined treatment with imetelstat and Alvespimycin on long-term growth was assessed in osteosarcoma cell lines (143B, HOS and MG-63) and xenografts derived from 143B cells. Results indicated that imetelstat as a single agent inhibited telomerase activity, induced telomere shortening, and inhibited growth in all 3 osteosarcoma cell lines, though the bulk cell cultures did not undergo growth arrest. Combined treatment with imetelstat and Alvespimycin resulted in diminished telomerase activity and shorter telomeres compared to either agent alone as well as higher levels of gammaH2AX and cleaved caspase-3, indicative of increased DNA damage and apoptosis. With dual telomerase and HSP90 inhibition, complete growth arrest of bulk cell cultures was achieved. In xenograft models, all 3 treatment groups significantly inhibited tumor growth compared with the placebo-treated control group, with the greatest effect seen in the combined treatment group (imetelstat, p = 0.045, Alvespimycin, p = 0.034; combined treatment, p = 0.004). In conclusion, HSP90 inhibition enhanced the effect of telomerase inhibition in pre-clinical models of osteosarcoma. Dual targeting of telomerase and HSP90 warrants further investigation as a therapeutic strategy.
Discovery of the neuroprotective effects of alvespimycin by computational prioritization of potential anti-Parkinson agents.[Pubmed:24304935]
FEBS J. 2014 Feb;281(4):1110-22.
Based on public gene expression data, we propose a computational approach to optimize gene expression signatures for the use with Connectivity Map (CMap) to reposition drugs or discover lead compounds for Parkinson's disease. This approach integrates genetic information from the Gene Expression Omnibus (GEO) database, the Parkinson's disease gene expression database (ParkDB), the Online Mendelian Inheritance in Man (OMIM) database and the Comparative Toxicogenomics Database (CTD), with the aim of identifying a set of interesting genes for use in computational drug screening via CMap. The results showed that CMap, using the top 20 differentially expressed genes identified by our approach as a gene expression signature, outperformed the same method using all differentially expressed genes (n = 535) as a signature. Utilizing this approach, the candidate compound Alvespimycin (17-DMAG) was selected for experimental evaluation in a model of rotenone-induced toxicity in human SH-SY5Y neuroblastoma cells and isolated rat brain mitochondria. The results showed that 17-DMAG significantly attenuated rotenone-induced toxicity, as reflected by the increase of cell viability, the reduction of intracellular reactive oxygen species generation and a reduction in mitochondrial respiratory dysfunction. In conclusion, this computational method provides an effective systematic approach for drug repositioning or lead compound discovery for Parkinson's disease, and the discovery of the neuroprotective effects of 17-DMAG supports the practicability of this method.
A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans.[Pubmed:24471734]
Br J Pharmacol. 2014 Jun;171(11):2778-89.
BACKGROUND AND PURPOSE: Alvespimycin, a new generation of heat shock protein 90 (Hsp90) inhibitor in clinical trial, is a promising therapeutic agent for cancer. Pharmacokinetic models of Alvespimycin would help in the understanding of drug disposition, predicting drug exposure and interpreting dose-response relationship. In the present study we aimed to develop a physiologically based pharmacokinetic (PBPK) model of Alvespimycin in mice and evaluate the utility of the model for predicting Alvespimycin disposition in other species. EXPERIMENTAL APPROACH: A literature search was performed to collect pharmacokinetic data for Alvespimycin. A PBPK model was initially constructed to demonstrate the disposition of Alvespimycin in mice, and then extrapolated to rats and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters. KEY RESULTS: A PBPK model, employing a permeability-limited model structure and saturable tissue binding, was built in mice. It successfully characterized the time course of the disposition of Alvespimycin in mice. After extrapolation to rats, the model simulated the Alvespimycin concentration-time profiles in rat tissues with acceptable accuracies. Likewise, a reasonable match was found between the observed and simulated human plasma pharmacokinetics of Alvespimycin. CONCLUSIONS AND IMPLICATIONS: The PBPK model described here is beneficial to the understanding and prediction of the effects of Alvespimycin in different species. It also provides a good basis for further development, which necessitates additional studies, especially those needed to clarify the in-depth mechanism of Alvespimycin elimination. A refined PBPK model would benefit the understanding of dose-response relationships and optimization of dosing regimens.
