| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 50mg | |||
| Other Sizes |
| Targets |
HSP90:119 nM (EC50); GRP94:119 nM (EC50)
Heat shock protein 90 (HSP90). HSP90 is a molecular chaperone that maintains the stability and functional conformation of numerous client proteins, including many oncogenic signaling proteins that may be overexpressed or overactive in tumor cells. By inhibiting HSP90, Retaspimycin promotes the degradation of these client proteins, leading to anti-tumor effects. |
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| ln Vitro |
Retaspimycin (IPI-504) is a Hsp90 inhibitor and a new, highly soluble derivative of 17AAG. In both tunicamycin (Tm)-treated and untreated U266 and MM.1s cells, retispimycin eliminates ERSE-driven luciferase activity and unfolded protein response element (UPRE). The IC50 of retaspimycin was found to be 196±56 nM in U266; 472±177 nM in MM.1s for UPRE-luc activity; and 213±140 nM in MM.1s cells for ERSE-driver activity. In line with the reporter gene experiment, retispimycin administration caused a dose-dependent drop in p50ATF6 with an EC50 of 237 nM. Retaspimycin causes sXBP1 levels to drop, with an apparent EC50 ranging from 300 nM to 1 μM [1]. Both trastuzumab-resistant and sensitive cells' Akt and MAPK phosphorylation are efficiently inhibited by retaspimycin (IPI-504) incubation. In all four cell lines (BT474, SKBR-3, HCC1569, and HCC1569), total Akt levels dropped in a dose-dependent way. Nonetheless, following retaspimycin treatment, overall MAPK levels did not significantly alter [2].
In vitro, Retaspimycin demonstrates potent HSP90 inhibition with an EC50 of 63 nM. The compound binds to and inhibits the cytosolic chaperone functions of HSP90. Its enhanced aqueous solubility compared to 17-AAG improves its in vitro handling and activity. Retaspimycin induces degradation of HSP90 client proteins and exhibits antiproliferative activity against various cancer cell lines. |
| ln Vivo |
In xenografts produced from trastuzumab-sensitive BT474 cells, retispimycin (IPI-504) and trastuzumab separately cause tumor regression. Transtuzumab did not stop the growth of xenografts made from BT474R cells, but they did not lose their sensitivity to retispimycin hydrochloride. Retaspimycin monotherapy gains minimal additional benefit from the combination of retaspimycin and trastuzumab. In HCC1569 xenografts, retaspimycin (100 mg/kg) was found to be a more potent single drug in suppressing tumor development than trastuzumab. Retaspimycin taken alone was not appreciably superior than the combination [2].
In vivo, Retaspimycin has been evaluated in preclinical models of cancer, including high-grade glioma models. The compound demonstrates antineoplastic and antiproliferative activities in tumor xenografts. Its enhanced solubility may improve its pharmacokinetic profile and efficacy compared to earlier HSP90 inhibitors. Retaspimycin has been studied in various cancer types, including solid tumors and hematologic malignancies. |
| Enzyme Assay |
Cell-free HSP90 binding assays for Retaspimycin use purified recombinant human HSP90 protein. The compound is incubated with HSP90 and a fluorescently labeled ATP-competitive probe at varying concentrations. Binding affinity is measured by fluorescence polarization or surface plasmon resonance (SPR). Competitive binding assays with ATP or other HSP90 inhibitors are performed to determine the mode of inhibition. IC50 and EC50 values are calculated from dose-response curves.
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| Cell Assay |
Cellular assays for Retaspimycin are performed using cancer cell lines (e.g., breast, prostate, or glioma cells). Cells are seeded in 96-well plates and treated with Retaspimycin at concentrations ranging from 0.01-100 μM for 24-72 hours. Cell viability is measured using MTT, CCK-8, or CellTiter-Glo assays. HSP90 client protein degradation (e.g., HER2, AKT, RAF-1) is assessed by Western blot analysis. HSP70 induction (a pharmacodynamic marker of HSP90 inhibition) is also measured. Apoptosis is quantified using Annexin V/PI staining or caspase-3/7 activity assays.
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| Animal Protocol |
In vivo efficacy studies are conducted in immunodeficient mice bearing subcutaneous xenografts of various cancer cell lines. Retaspimycin is administered via intravenous injection at doses typically ranging from 10-100 mg/kg, on a scheduled regimen (e.g., daily or weekly). Tumor volume is measured every 2-3 days using calipers. At study termination, tumors are excised and processed for immunohistochemistry or Western blot analysis to assess HSP90 client protein degradation and pharmacodynamic markers. Pharmacodynamic studies involve collecting tumors at various time points post-dose to measure target engagement.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of Retaspimycin demonstrate that the compound has significantly enhanced aqueous solubility compared to 17-AAG, which may improve its bioavailability and systemic exposure. PK parameters such as Cmax, Tmax, AUC, half-life, clearance, and volume of distribution are determined in preclinical species. The compound is administered intravenously in clinical studies. Its distribution includes tumor tissue, where it exerts its anti-tumor effects. Metabolism occurs via hepatic pathways.
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| Toxicity/Toxicokinetics |
Toxicology studies of Retaspimycin were conducted as part of its clinical development program. As an HSP90 inhibitor, potential toxicities include effects on normal tissues that depend on HSP90 client proteins for homeostasis, such as the gastrointestinal tract, liver, and bone marrow. Standard toxicology studies (acute, subchronic, and chronic) were performed in rodents and non-human primates. The compound's safety profile was evaluated in clinical trials. Specific toxicity findings are not widely reported in public sources.
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| References |
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| Additional Infomation |
Retaspimycin hydrochloride is the monohydrochloride salt of Retaspimycin. It is a semi-synthetic water-soluble analog of gerdemycin used for cancer treatment. It is an HSP90 inhibitor and an antitumor drug. It contains Retaspimycin (1+). Retaspimycin hydrochloride is the hydrochloride salt of heat shock protein 90 (HSP90), a small molecule inhibitor with antiproliferative and antitumor activities. Retaspimycin binds to HSP90 and inhibits its cytoplasmic molecular chaperone function. HSP90 maintains the stability and functional conformation of many oncogenic signaling proteins, which may be overexpressed or overactive in tumor cells. Retaspimycin-mediated HSP90 inhibition promotes proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which may lead to apoptosis.
Retaspimycin HCl (IPI-504) is a clinical-stage HSP90 inhibitor that was developed by Infinity Pharmaceuticals. It was investigated in clinical trials for various cancers, including non-small cell lung cancer, breast cancer, and multiple myeloma. The compound's enhanced solubility compared to 17-AAG was intended to improve its clinical utility. Although development was ultimately discontinued, Retaspimycin remains a valuable research tool for studying HSP90 biology. The compound is available for research purposes. |
| Molecular Formula |
C31H45N3O8.HCL
|
|---|---|
| Molecular Weight |
624.16524
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| Exact Mass |
623.297
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| Elemental Analysis |
C, 59.65; H, 7.43; Cl, 5.68; N, 6.73; O, 20.51
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| CAS # |
857402-63-2
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| Related CAS # |
Retaspimycin;857402-23-4
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| PubChem CID |
11685945
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| Appearance |
Off-white to pink solid powder
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| LogP |
6.093
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
43
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| Complexity |
999
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| Defined Atom Stereocenter Count |
6
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| SMILES |
C[C@H]1C[C@@H]([C@@H]([C@H](/C=C(/[C@@H]([C@H](/C=C\C=C(\C(=O)NC2=CC(=C(C(=C2O)C1)NCC=C)O)/C)OC)OC(=O)N)\C)C)O)OC.Cl
|
| InChi Key |
OIRUWDYJGMHDHJ-AFXVCOSJSA-N
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| InChi Code |
InChI=1S/C31H45N3O8.ClH/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);1H/b11-9-,18-10+,20-15+;/t17-,19+,24+,25+,27-,29+;/m1./s1
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| 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;hydrochloride
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| Synonyms |
retaspimycin hydrochloride; Retaspimycin HCl; IPI-504; 857402-63-2; IPI-504 HYDROCHLORIDE;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
1M HCl : 100 mg/mL (~160.21 mM)
DMSO : ~60 mg/mL (~96.13 mM) H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 3 mg/mL (4.81 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6021 mL | 8.0106 mL | 16.0213 mL | |
| 5 mM | 0.3204 mL | 1.6021 mL | 3.2043 mL | |
| 10 mM | 0.1602 mL | 0.8011 mL | 1.6021 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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