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17-DMAG Sale

(Synonyms: 阿螺旋霉素; 17-DMAG; NSC 707545) 目录号 : GC41955

Water-soluble inhibitor of Hsp90

17-DMAG Chemical Structure

Cas No.:467214-20-6

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实验参考方法

Cell experiment:

MTT assays are performed to determine cytotoxicity. A total of 1×106 CD19-selected B cells from CLL patients are incubated for 24 or 48 hours in Alvespimycin, 17-AAG, or vehicle. MTT reagent is then added, and plates are incubated for an additional 24 hours before spectrophotometric measurement. Apoptosis is determined by staining with annexin V-fluorescein isothiocyanate and propidium iodide (PI). After exposure to drugs, cells are washed with phosphate-buffered saline and stained in 1 time binding buffer. Cell death is assessed by flow cytometry. Data are analyzed with the System II software package. A total of 10000 cells are counted for each sample. Mitochondrial membrane potential changes are assessed by staining with the lipophilic cationic dye JC-1 and analysis by flow cytometry[2].

Animal experiment:

Mice[3]Young male CB-17/IcrHsd-Prkdc-SCID mice are used. Recombinant xenografts are made by mixing 1×105 BPH1 cells and 2.5×105 CAF per graft in collagen solution, allowed to gel, covered with medium and cultured overnight. Tumors are allowed to form over eight weeks, and then treated for four weeks with three different doses of dipalmitoyl-radicicol (50, 100 and 200 mg/kg) and Alvespimycin (5, 10 and 20 mg/kg) via intraperitoneal injections of compounds in sesame oil every four days. After 12 weeks in total, the mice are sacrificed, their kidneys resected, grafts cut in half and photographed before processing for histology. Graft dimensions are measured and the resultant tumour volume is calculated using the formula; volume=width × length × depth × π/6. This formula represents a conservative approach to evaluate tumour volumes, as it understates the volume of large, invasive tumours compared with smaller, non-invasive tumours. Resected grafts are fixed in 10% formalin, embedded in paraffin and processed for immunohistochemistry.

References:

[1]. Ge J, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem. 2006 Jul 27;49(15):4606-15.
[2]. Hertlein E, et al. 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.
[3]. Henke A, et al. Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90. Cancers (Basel). 2016 Aug 24;8(9). pii: E77.

产品描述

Alvespimycin (17-DMAG) is a potent inhibitor of Hsp90, binding to Hsp90 with an EC50 of 62 ± 29 nM.

Alvespimycin (17-DMAG) 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 (17-DMAG) 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 (17-DMAG) 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 (17-DMAG) is much more potent after 24 and 48 hours of treatment than 17-AAG[2].

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 (17-DMAG). 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 (17-DMAG) at either 10 or 20 mg/kg elicits a significant reduction in tumor size[3].

References:
[1]. Ge J, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem. 2006 Jul 27;49(15):4606-15.
[2]. Hertlein E, et al. 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.
[3]. Henke A, et al. Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90. Cancers (Basel). 2016 Aug 24;8(9). pii: E77.

Chemical Properties

Cas No. 467214-20-6 SDF
别名 阿螺旋霉素; 17-DMAG; NSC 707545
Canonical SMILES O=C(C(NCCN(C)C)=C1C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(C)/[C@@H]2OC(N)=O)C=C(NC(/C(C)=C/C=C\[C@@H]2OC)=O)C1=O
分子式 C32H48N4O8 分子量 616.8
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Research Update

Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art

Biomed Pharmacother 2018 Jun;102:608-617.PMID:29602128DOI:10.1016/j.biopha.2018.03.102.

Heat shock protein 90 (Hsp90) is an evolutionary preserved molecular chaperone which mediates many cellular processes such as cell transformation, proliferation, and survival in normal and stress conditions. Hsp90 plays an important role in folding, maturation, stabilization and activation of Hsp90 client proteins which all contribute to the development, and proliferation of cancer as well as other inflammatory diseases. Functional inhibition of Hsp90 can have a massive effect on various oncogenic and inflammatory pathways, and will result in the degradation of their client proteins. This turns it into an interesting target in the treatment of different malignancies. 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) as a semi-synthetic derivative of geldanamycin, has several advantages over 17-Allylamino-17-demethoxygeldanamycin (17-AAG) such as higher water solubility, good bioavailability, reduced metabolism, and greater anti-tumour capability. 17-DMAG binds to the Hsp90, and inhibits its function which eventually results in the degradation of Hsp90 client proteins. Here, we reviewed the pre-clinical data and clinical trial data on 17-DMAG as a single agent, in combination with other agents and loaded on nanomaterials in various cancers and inflammatory diseases.

The HSP90 inhibitor 17-DMAG alleviates primary biliary cholangitis via cholangiocyte necroptosis prevention

J Cell Biochem 2022 Nov;123(11):1857-1872.PMID:36037317DOI:10.1002/jcb.30321.

Cholangiocyte death accompanied by the progression of primary biliary cholangitis (PBC) has not yet been thoroughly investigated. Thus, we are aimed to explore the role of HSP90 and a potential treatment strategy in cholangiocyte necroptosis. First, we detected the expression of HSP90 and necroptotic markers in liver tissues from patients and mice with PBC by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR). Then, the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), was administered by intraperitoneal injection to evaluate its therapeutic effect for PBC by IHC, real-time PCR, and western blotting. Human intrahepatic bile duct epithelial cells (HIBECs) were induced to necroptosis by toxic bile acid and lipopolysaccharide (LPS) treatment, and evaluated via Cell Counting Kit-8 and flow cytometry assays. Additionally, 17-DMAG, cycloheximide, and a proteasome inhibitor were used to evaluate the role of HSP90 in cholangiocyte necroptosis. We found that the expression of HSP90 was elevated in the cholangiocytes of patients and mice with PBC, along with higher expressions of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated-MLKL (p-MLKL). Proinflammatory cytokines and antibody levels of the E2 subunit of pyruvate dehydrogenase complex decreased after treatment with 17-DMAG in PBC mice. Meanwhile, RIPK1, RIPK3, phosphorylated-RIPK3, MLKL, and p-MLKL protein expressions decreased with 17-DMAG treatment. In vitro, 17-DMAG and necrostatin-1 prevented glycochenodeoxycholic acid and LPS-induced necroptosis of HIBECs. Immunoprecipitation and high-performance liquid chromatography-mass spectrometry analysis showed that RIPK1 combined with HSP90. Additionally, the 17-DMAG treatment reduced the RIPK1 half-life. Overall, 17-DMAG might be a potential therapeutic agent for PBC via cholangiocyte necroptosis prevention by accelerating RIPK1 degradation.

17-DMAG Protects Against Hypoxia-/Reoxygenation-Induced Cell Injury in HT22 Cells Through Akt/Nrf2/HO-1 Pathway

DNA Cell Biol 2017 Feb;36(2):95-102.PMID:27982695DOI:10.1089/dna.2016.3445.

Oxidative stress is well known to play a pivotal role in hypoxia/reoxygenation (H/R)-induced neuron injury. On the basis of this fact, antioxidative agents have been demonstrated to be neuroprotective. 17-DMAG (HSP90 inhibitor) is reported to have neuroprotective effects in vitro, which may interfere with oxidative stress through reduction in pro-oxidative factors. However, little is known about its effects on H/R-induced neuron injury and the underlying mechanisms. In this study, the effects of 17-DMAG on H/R-treated HT22 cells were investigated. MTT and lactate dehydrogenase (LDH) assays indicated that 17-DMAG led to a dose-dependent recovery of cell viability in H/R-treated HT22 cells. Flow cytometry demonstrated that 17-DMAG inhibited the cell apoptosis induced by H/R in HT22 cells. In addition, Western blot and real-time reverse transcription-polymerase chain reaction indicated that 17-DMAG inhibited the H/R-induced upregulation of Bax/Bcl-2 ratio and cleaved caspase-3 expression. Moreover, our results demonstrated that 17-DMAG promoted the expression of antioxidant enzymes, including manganese superoxide dismutase, catalase, and glutathione peroxidase. As a result, 17-DMAG might resist to H/R-induced oxidative stress. Furthermore, 17-DMAG increased the expression of phosphorylation of Akt (p-Akt) and the heme oxygenase-1 (HO-1), as well as the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in H/R-treated HT22 cells. However, the Akt inhibitor, LY294002, partially hampered the effects of 17-DMAG on the expression of p-Akt, nuclear Nrf2, and HO-1 and cell viability, as well as cell apoptosis induced by H/R in HT22 cells. In conclusion, the findings of our study thus demonstrate that 17-DMAG protects against H/R-induced HT22 cell injury through Akt/Nrf2/HO-1 pathway, which may be associated with its antiapoptotic and antioxidative stress effects.

17-DMAG, an Hsp90 inhibitor, ameliorates ovariectomy-induced obesity in rats

Life Sci 2019 Sep 1;232:116672.PMID:31336120DOI:10.1016/j.lfs.2019.116672.

Aims: Obesity is not only associated with metabolic diseases but is also a symptom of menopause in women. To date, there are no effective drugs for the management of obesity, and it is important to find new agents with fewer side effects, for the treatment of obesity. This study aimed to determine the anti-obesity effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, and its underlying mechanism in rats with ovariectomy-induced obesity. Main methods: Ovariectomy (Ovx) rats were treated with 17-DMAG (1 mg kg-1, intraperitoneally) for eight weeks from one week after surgery. The body weight, food intake, locomotor activity, adipogenic- and autophagy-related protein expression in white adipose tissue (WAT) and plasma triglyceride (TG) levels were measured in sham and Ovx rats. Key findings: Compared with sham rats, Ovx rats showed increased weight gain, food intake, WAT mass, TG levels, adipogenic protein expression, and decreased locomotor activity. Furthermore, autophagy-related proteins and Foxo3a of WAT were significantly increased in Ovx rats. However, with the exclusion of increased food intake, the changes induced by Ovx were all reversed in 17-DMAG-treated Ovx rats. In addition, the expression of Hsp70 and phosphorylation of Akt increased in 17-DMAG-treated Ovx rats. Significance: These results suggest that 17-DMAG significantly ameliorated obesity induced by Ovx, and this phenomenon is accompanied by the downregulation of adipogenic-related and autophagy-related proteins as well as the upregulation of Akt-phosphorylation and Hsp70 expression. Therefore, 17-DMAG may be a potential agent for preventing or treating obesity in postmenopausal women.

17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma

iScience 2020 Dec 28;24(1):101996.PMID:33490904DOI:10.1016/j.isci.2020.101996.

Histone lysine demethylases (KDMs) play critical roles in oncogenesis and therefore may be effective targets for anticancer therapy. Using a time-resolved fluorescence resonance energy transfer demethylation screen assay, in combination with multiple orthogonal validation approaches, we identified geldanamycin and its analog 17-DMAG as KDM inhibitors. In addition, we found that these Hsp90 inhibitors increase degradation of the alveolar rhabdomyosarcoma (aRMS) driver oncoprotein PAX3-FOXO1 and induce the repressive epigenetic mark H3K9me3 and H3K36me3 at genomic loci of PAX3-FOXO1 targets. We found that as monotherapy 17-DMAG significantly inhibits expression of PAX3-FOXO1 target genes and multiple oncogenic pathways, induces a muscle differentiation signature, delays tumor growth and extends survival in aRMS xenograft mouse models. The combination of 17-DMAG with conventional chemotherapy significantly enhances therapeutic efficacy, indicating that targeting KDM in combination with chemotherapy may serve as a therapeutic approach to PAX3-FOXO1-positive aRMS.