Retaspimycin

HSP90 inhibitor,antiproliferative and antineoplastic CAS# 857402-23-4

Retaspimycin

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Chemical structure

Retaspimycin

3D structure

Chemical Properties of Retaspimycin

Cas No. 857402-23-4 SDF Download SDF
PubChem ID 11534420 Appearance Powder
Formula C31H45N3O8 M.Wt 587.7
Type of Compound N/A Storage Desiccate at -20°C
Synonyms IPI-504
Solubility Soluble in DMSO
Chemical Name [(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13,20,22-trihydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3-oxo-19-(prop-2-enylamino)-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18(22),19-hexaen-9-yl] carbamate
SMILES CC1CC(C(C(C=C(C(C(C=CC=C(C(=O)NC2=CC(=C(C(=C2O)C1)NCC=C)O)C)OC)OC(=O)N)C)C)O)OC
Standard InChIKey OAKGNIRUXAZDQF-TXHRRWQRSA-N
Standard InChI InChI=1S/C31H45N3O8/c1-8-12-33-26-21-13-17(2)14-25(41-7)27(36)19(4)15-20(5)29(42-31(32)39)24(40-6)11-9-10-18(3)30(38)34-22(28(21)37)16-23(26)35/h8-11,15-17,19,24-25,27,29,33,35-37H,1,12-14H2,2-7H3,(H2,32,39)(H,34,38)/b11-9-,18-10+,20-15+/t17-,19+,24+,25+,27-,29+/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.
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.
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.

Biological Activity of Retaspimycin

DescriptionRetaspimycin is a small-molecule inhibitor of heat shock protein 90 (HSP90).
TargetsHSP90    

Protocol

Cell Assay [3]
Cell proliferation is studied using the cell proliferation reagent WST-1. Briefly, 8 × 103 cells are seeded in triplicate in 96-well plates and treated for 5 days, with either trastuzumab or Retaspimycin as indicated. Viable cells are estimated on the basis of their ability to metabolize tetrazolium salt WST-1 to formazan by mitochondrial dehydrogenases. Quantification of the formazan dye directly correlates with the number of metabolically active cells and is analyzed by a scanning microplate reader. Results are shown as means ± SE[3].

Animal Administration [1]
RPMI-8226 cells are harvested from cultures grown in vitro in RPMI medium 1640 supplemented with heat-inactivated 10% (wt/vol) FBS and 100 units/mL penicillin/streptomycin at 37°C under a humidified 95%/5% (vol/vol) mixture of air and CO2. Cells are washed twice by using sterile Hepes-buffered saline (HBS) and suspended in HBS to a concentration of 1 × 108 viable cells per mL. Twelve female Nu/Nu nude mice (≈20 g) are used in the assay. RPMI-8226 cells (1 × 107 cells per mouse) are implanted in the right flank. When tumor volume reaches ≈200-500 mm3 (≈4 weeks postimplantation), animals receive a single i.v. dose of 50 mg/kg Retaspimycin via the tail vein. At 4, 24, and 48 h posttreatment, the animals are killed with carbon dioxide, and tumors are removed and stored at −80°C until analyzed. Four animals are used for each time point. Tumor samples are homogenized in an ice-cold, nitrogen-sparged 1:1 solution of MeOH:150 mM citrate, 0.2% (wt/vol) EDTA, and 0.2% (wt/vol) ascorbate (pH 3.0) for 1 min in an ice/water bath with a homogenizer at 17,500 rpm. Samples are centrifuged for 5 min at 4°C at 18,000 × g. The supernatants are diluted 1:1 with ice-cold, nitrogen-sparged 75 mM citrate, 0.1% (wt/vol) EDTA, and 0.1% (wt/vol) ascorbate (pH 3) containing 25 ng/mL deuterated 17-AAG as internal standard and analyzed by LC-MS/MS analysis. The standard curve is prepared for Retaspimycin, 17-AAG, and 17-AG in 1:1 MeOH:150 mM citrate, 0.2% (wt/vol) EDTA, and 0.2% (wt/vol) ascorbate (pH 3.0); diluted 1:1 with ice-cold, nitrogen-sparged 75 mM citrate, 0.1% (wt/vol) EDTA, and 0.1% (wt/vol) ascorbate (pH 3.0) containing 25 ng/mL deuterated 17-AAG as internal standard; and analyzed by LC-MS/MS[1].

References:
[1]. Sydor JR, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17408-13. Epub 2006 Nov 7. [2]. Floris G, et al. The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors. Mol Cancer Ther. 2011 Oct;10(10):1897-908. [3]. Scaltriti M, et al. Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer. Mol Cancer Ther. 2011 May;10(5):817-24.

Retaspimycin Dilution Calculator

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Retaspimycin Molarity Calculator

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Preparing Stock Solutions of Retaspimycin

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7015 mL 8.5077 mL 17.0155 mL 34.031 mL 42.5387 mL
5 mM 0.3403 mL 1.7015 mL 3.4031 mL 6.8062 mL 8.5077 mL
10 mM 0.1702 mL 0.8508 mL 1.7015 mL 3.4031 mL 4.2539 mL
50 mM 0.034 mL 0.1702 mL 0.3403 mL 0.6806 mL 0.8508 mL
100 mM 0.017 mL 0.0851 mL 0.1702 mL 0.3403 mL 0.4254 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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Background on Retaspimycin

Retaspimycin is a water-soluble hydroquinone hydrochloride salt inhibitor of Hsp90 [1].

Hsp90 is a member of the Hsp family. The other members of this protein family are Hsp40, Hsp70 and so on. These proteins act as molecule chaperons and participate in many cellular processes. When cells are exposed in stress, some proteins become unstable, accumulate to form aggregates and subsequently cause cell apoptosis. In this situation, Hsps will help their client proteins folding correctly, accompany them to be translocated to the correct location and thus prevent the cells from apoptosis. Hsps are required for cancer cells development. They are found to overexpress in a variety of cancer cells. Therefore, the inhibitors of Hsp are thought to be attractive therapy for cancer treatment. As an inhibitor of Hsp90, retaspimycin works through binding to the ATP-binding pocket of Hsp90 N-terminal [1].

In both RPMI-8826 and MM1.S cells, treatment of retaspimycin resulted in degradation of the Hsp90 client proteins, for instance, c-RAF and Her2. It also caused increased levels of Hsp70. Besides that, retaspimycin is found to prevent RPMI-8826 cells from secreting the immunoglobulin light chain. In breast cancer cells which are resistant to trastuzumab, treatment of retaspimycin potently caused Her2 degradation and resulted in tumor growth suppression and cell apoptosis [1].

Retaspimycin is often used as combination therapy with other drugs in cancer treatment. In mice bearing GIST-882 (gastrointestinal stromal tumor) xenografts, the administration of retaspimycin associated with imatinib showed a significant effect with a 66% tumor regression. In mice bearing GIST-PSW xenografts, both the combination treatment of retaspimycin and imatinib or sunitinib showed effective antitumor activities in reducing tumor burden. When used alone, retaspimycin reduced tumor volumes by 84% and 69% in GIST-PSW and GIST-882 mice models, respectively. Moreover, retaspimycin is found to decrease the mitotic activity in these two models. However, the antimitotic effects of retaspimycin were less significant than of imatinib or sunitinib or the combination treatment [2].

References:
[1].  Hanson B E, Vesole D H. Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent. 2009.
[2].  Floris G, Debiec-Rychter M, Wozniak A, et al. The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors. Molecular cancer therapeutics, 2011, 10(10): 1897-1908.

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References on Retaspimycin

Multicenter phase II trial of the heat shock protein 90 inhibitor, retaspimycin hydrochloride (IPI-504), in patients with castration-resistant prostate cancer.[Pubmed:21762967]

Urology. 2011 Sep;78(3):626-30.

OBJECTIVE: To evaluate clinical activity and safety of Retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC). METHODS: A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if >/=1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout. RESULTS: A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively. CONCLUSION: Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.

A phase 1 study of IPI-504 (retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma.[Pubmed:21851215]

Leuk Lymphoma. 2011 Dec;52(12):2308-15.

Abstract A phase 1 study of IPI-504 (Retaspimycin hydrochloride) administered intravenously twice weekly for 2 weeks at 22.5, 45, 90, 150, 225, 300 or 400 mg/m(2) followed by 10 days off-treatment was conducted to determine the safety and maximum tolerated dose (MTD) of IPI-504 in patients with relapsed or relapsed/refractory multiple myeloma (MM). Anti-tumor activity and pharmacokinetics were also evaluated. Eighteen patients (mean age 60.5 years; median 9 prior therapies) were enrolled. No dose-limiting toxicities (DLTs) were reported for IPI-504 doses up to 400 mg/m(2). The most common treatment-related adverse event was grade 1 infusion site pain (four patients). All other treatment-related events were assessed as grade 1 or 2 in severity. The area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2-4 h for IPI-504 and its metabolites. Four patients had stable disease, demonstrating modest single-agent activity in relapsed or relapsed/refractory MM.

A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer.[Pubmed:23580070]

Breast Cancer Res Treat. 2013 May;139(1):107-13.

Heat shock protein 90 (Hsp90) facilitates maturation and stability of HER2. Combining an Hsp90 inhibitor and trastuzumab has demonstrated anti-tumor effects in patients with HER2+ breast cancer. Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m(2) Retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks. A Simon's two-stage design determined trial expansion by dose-limiting toxicity (DLT) and response rates. Pharmacokinetics and electrocardiograms were evaluated. Twenty-six patients with median age 52.5 years (range 33-72) enrolled with a median of six prior chemotherapeutic regimens (range 2-20). On study, patients received a median of three treatment cycles (range 1-12). No DLTs were observed. Most adverse events (AEs) were grade 1 or 2; common treatment-related AEs included fatigue (46 %), nausea (31 %), and diarrhea (23 %). One patient had treatment-related serious AEs of grade 1 diarrhea and grade 3 hypokalemia. grade 3 transaminase elevation occurred in one patient (4 %) who also had metastatic liver disease. Sixteen patients (62 %) had stable disease, with a median on-study duration of 2.4 months (range 1.1-8.2). No confirmed responses were observed. Retaspimycin HCl at 300 mg/m(2) weekly in combination with trastuzumab was well tolerated and without significant toxicities. Modest clinical activity was observed, but did not meet criteria for trial expansion. The safety profile for patients on study raises the possibility of Retaspimycin HCl underdosing that limited efficacy. Studies employing higher doses are ongoing.

A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas.[Pubmed:24045182]

Clin Cancer Res. 2013 Nov 1;19(21):6020-9.

PURPOSE: Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRalpha) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of Retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). EXPERIMENTAL DESIGN: IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. RESULTS: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. CONCLUSIONS: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.

Description

Retaspimycin is a potent and water-soluble inhibitor of Hsp90, with EC50s of 119 nM for both Hsp90 and Grp9.

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