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| Targets |
HSP90 51 nM (IC50, MDA-MB-468 cells)
Zelavespib hydrochloride targets the ATP-binding pocket of heat shock protein 90 (Hsp90). It is a potent inhibitor, with an IC50 of 51 nM in MDA-MB-468 breast cancer cells. Hsp90 is a molecular chaperone that stabilizes and activates many client proteins involved in cancer cell growth and survival (e.g., HER2, Akt, Raf-1, mutant p53). By inhibiting Hsp90, Zelavespib causes the degradation of these client proteins, leading to cancer cell death. It also inhibits proliferation of many tumor cells, with IC50s of 65 +/- 8 nM (MDA-MB-468), 140 +/- 5 nM (MDA-MB-231), and 87 +/- 3 nM (HCC-1806). |
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| ln Vitro |
Zelavespib hydrochloride has an IC50 of 51 nM in MDA-MB-468 cells, making it a strong Hsp90 inhibitor. Zelavespib suppresses the proliferation of many tumor cells, with IC50s of 65 ± 8 nM, 140 ± 5 nM, and 87 ± 3 nM, respectively, against MDA-MB-468, MDA-MB-231, and HCC-1806 cells. This inhibition is in line with the related G2-M blockage. Triple-negative breast cancer (TNBC) is significantly apoptotic when zelavespib (10-1000 nM) is administered. Additionally, zelavespib (0.5, 1 μM) downregulates oncoproteins linked to TNBC's capacity for invasion [1]. BCR signaling kinase is reduced and depleted by zelavespib (0.5 μM). Zelavespib (0.25–10 μM) has little effect on resting B cells or PBMC, but it is cytotoxic to CLL cells. Furthermore, at 0.5 μM, zelavespib (0-1μM) antagonizes survival signals from the CLL microenvironment and decreases CLL viability by causing mitochondrial apoptosis [2]. TNF-α boosted the induction of apoptosis in MDA-MB-231, BT-474, and MCF7 cells induced by zelavespib (0.05 μM). Zelavespib (0.05 μM) has the ability to inhibit TNF-α-induced NF-κB transcriptional activity and degrade IKKβ [3].
In vitro, Zelavespib hydrochloride potently inhibits Hsp90 with an IC50 of 51 nM in MDA-MB-468 cells. It suppresses the proliferation of many tumor cell lines, including breast cancer cells, with IC50s of 65 nM (MDA-MB-468), 140 nM (MDA-MB-231), and 87 nM (HCC-1806). Zelavespib is a novel purine-based Hsp90 inhibitor and acts as a radiosensitizer, making it a promising candidate for carbon ion radiotherapy (CIRT). It induces degradation of Hsp90 client proteins and shows antitumor activity in many preclinical cancer models. |
| ln Vivo |
Zelavespib (75 mg/kg, i.p.) in tumor-bearing MDA-MB-468 mice resulted in intratumoral accumulation, extended downregulation of antitumor driving molecules, and completed and preserved responses at nontoxic levels. Tumor growth is inhibited by zelavespib (75 mg/kg, intraperitoneally, for 3 weeks), which is linked to the downregulation of several malignant kinesins controlled by Hsp90 [1].
In vivo, Zelavespib hydrochloride has demonstrated antitumor activity in preclinical models of lymphoma and solid tumors. It has been tested in clinical trials against lymphoma and solid tumors. The compound is administered as an intravenous infusion over 1 hour, typically twice a week at doses ranging from 10 mg/m2 to 470 mg/m2. It shows dose-dependent pharmacokinetics and is generally well-tolerated in clinical studies. The antitumor efficacy and safety profile are still under investigation in ongoing trials. |
| Enzyme Assay |
For in vitro Hsp90 inhibition assays, the Hsp90 inhibitor activity is determined using a fluorescence polarization (FP) assay or a luminescence-based ATPase assay. Recombinant Hsp90 protein is incubated with a fluorescent Hsp90 ligand (e.g., FITC-geldanamycin) in the presence of varying concentrations of Zelavespib hydrochloride (0.1-1000 nM). After incubation at room temperature for 1-2 hours, fluorescence polarization is measured. The IC50 is calculated from the dose-response curve.
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| Cell Assay |
For cell-based assays, breast cancer cells (MDA-MB-468, MDA-MB-231, HCC-1806) are seeded in 96-well plates and treated with Zelavespib hydrochloride at concentrations of 0.001-100 microM for 48-72 hours. Cell viability is assessed by MTT or CellTiter-Glo assays. Degradation of Hsp90 client proteins (e.g., HER2, Akt, Raf-1) is assessed by Western blot of cell lysates after 24-48 hours of treatment. Apoptosis is measured by Annexin V/PI staining or caspase-3/7 activity assays.
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| Animal Protocol |
For in vivo studies in xenograft mouse models, cancer cells are subcutaneously implanted into immunodeficient mice. When tumors reach a certain volume, mice are treated with Zelavespib hydrochloride via intraperitoneal injection or intravenous infusion at doses of 50-150 mg/kg, typically once daily or on a schedule (e.g., 5 days on, 2 days off). Tumor volume is measured with calipers twice weekly. Body weight is monitored for toxicity. At study termination, tumors are excised for analysis of Hsp90 client protein levels and apoptosis markers.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in human clinical trials have characterized Zelavespib (PU-H71). After intravenous infusion at doses of 10-470 mg/m2, the plasma Cmax ranges from 0.2 microM to 33.7 microM, and the AUC ranges from 31 to 12151 microM·min. The terminal half-life (t1/2) ranges from 2.7 to 11.5 hours, depending on the dose. The compound is administered as an intravenous infusion. Zelavespib hydrochloride is soluble in DMSO and should be stored at -20degC as a powder, protected from light.
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| Toxicity/Toxicokinetics |
Clinical trial data indicate that Zelavespib has an acceptable safety profile at doses up to 470 mg/m2. Common adverse events include fatigue, nausea, diarrhea, and liver enzyme elevations. At higher doses, dose-limiting toxicities (DLTs) may occur, including hepatotoxicity and thrombocytopenia. The overall safety profile is consistent with other Hsp90 inhibitors. As a research compound, standard safety precautions should be followed.
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| References |
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| Additional Infomation |
Zelavespib hydrochloride (PU-H71 hydrochloride) is an investigational drug that has been studied in clinical trials for lymphoma and solid tumors. It is not yet approved for clinical use. The compound is a novel, purine-based, ATP-competitive Hsp90 inhibitor that differs structurally from geldanamycin derivatives. It has shown radiosensitizing properties, making it of interest for combination with radiotherapy. The CAS number is 2095432-24-7. Store as a powder at -20degC, protected from light and moisture.
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| Molecular Formula |
C18H22CLIN6O2S
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|---|---|
| Molecular Weight |
548.83
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| Exact Mass |
548.026
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| CAS # |
2095432-24-7
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| Related CAS # |
Zelavespib;873436-91-0
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| PubChem CID |
54613037
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
29
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| Complexity |
520
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)NCCCN1C2=NC=NC(=C2N=C1SC3=C(C=C4C(=C3)OCO4)I)N.Cl
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| InChi Key |
HUAKDRZHOBLKGD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H21IN6O2S.ClH/c1-10(2)21-4-3-5-25-17-15(16(20)22-8-23-17)24-18(25)28-14-7-13-12(6-11(14)19)26-9-27-13;/h6-8,10,21H,3-5,9H2,1-2H3,(H2,20,22,23);1H
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| Chemical Name |
8-[(6-iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[3-(propan-2-ylamino)propyl]purin-6-amine;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) |
H2O :~15.38 mg/mL (~28.02 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8221 mL | 9.1103 mL | 18.2206 mL | |
| 5 mM | 0.3644 mL | 1.8221 mL | 3.6441 mL | |
| 10 mM | 0.1822 mL | 0.9110 mL | 1.8221 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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