PU-WS13 |
| Katalog-Nr.GC13307 |
Grp94-spezifischer Hsp90-Inhibitor
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1454619-14-7
Sample solution is provided at 25 µL, 10mM.
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PU-WS13 is a purine scaffold-based Grp94-specific heat shock protein 90 (Hsp90) inhibitor[1]. In humans, Hsp90α and Hsp90β in the cytoplasm, Grp94 in the endoplasmic reticulum, and Trap-1 in the mitochondria are the four Hsp90 paralogs[2]. The mechanism of action of PU-WS13 is to block the formation of the Grp94-IgG complex by occupying the ATP site in Grp94[3].
In vitro, treatment of M2 macrophages with PU-WS13 (25μM) for 72h blocked Grp94 secretion induced by thapsigargin (Tg), attenuated endoplasmic reticulum (ER) stress, reduced the secretion of proinflammatory factors IFNγ, IL-6, and TNFα, and reduced intracellular cathepsin L[4]. Treatment of MV4-11 cells expressing FLT3-ITD with PU-WS13 (50μM) for 24h significantly reduced cell survival and induced cell membrane translocation[5].
In vivo, treatment of wild-type mice with PU-WS13 (15mg/kg) by intraperitoneal injection inhibited Grp94, thereby limiting tumor growth and collagen content, and increased the number of CD8+ cells in the tumor microenvironment (TME)[6]. Intratracheal treatment of mice co-infected with influenza A virus and Streptococcus pneumoniae with PU-WS13 (20mg/kg) significantly reduced bacterial colonization in the lungs, improved lung pathology, and restored E-cadherin expression in lung tissues[7].
References:
[1] Wu B X, Hong F, Zhang Y, et al. GRP94/gp96 in cancer: biology, structure, immunology, and drug development[J]. Advances in cancer research, 2016, 129: 165-190.
[2] Patel P D, Yan P, Seidler P M, et al. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2[J]. Nature chemical biology, 2013, 9(11): 677-684.
[3] Tramentozzi E, Finotti P. Effects of purine-scaffold inhibitors on HUVECs: Involvement of the purinergic pathway and interference with ATP. Implications for preventing the adverse effects of extracellular Grp94[J]. Biochemistry and Biophysics Reports, 2019, 19: 100661.
[4] Chaumonnot K, Masson S, Sikner H, et al. The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress[J]. Cell death & disease, 2021, 12(1): 114.
[5] Wang F, Baverel V, Chaumonnot K, et al. The endoplasmic reticulum stress protein GRP94 modulates cathepsin L activity in M2 macrophages in conditions of obesity-associated inflammation and contributes to their pro-inflammatory profile[J]. International Journal of Obesity, 2024: 1-11.
[6] Bouchard A, Sikner H, Baverel V, et al. The GRP94 inhibitor PU-WS13 decreases M2-like macrophages in murine TNBC tumors: a pharmaco-imaging study with 99mTc-Tilmanocept SPECT[J]. Cells, 2021, 10(12): 3393.
[7] Sumitomo T, Nakata M, Nagase S, et al. GP96 drives exacerbation of secondary bacterial pneumonia following influenza A virus infection[J]. Mbio, 2021, 12(3): 10.1128/mbio. 03269-20.
| Cell experiment [1]: | |
Cell lines | M1 and M2 macrophages |
Preparation Method | M1 and M2 macrophages from PBMC healthy volunteers were activated in the presence of GM-CSF and M-CSF, respectively. Thapsigargin (Tg) was added to cell cultures during the 48h activation period. PU-WS13 or DMSO as vehicle was added in cell culture medium at the concentration of 25μM 24h before and during all the activation period. CD80 and CD206 analysis by flow cytometry. |
Reaction Conditions | 25μM; 72h |
Applications | PU-WS13 at the concentration of 25μM prevented both the increase in CD80 and the decrease in CD206 in Tg-treated M2. PU-WS13 did not induce any change in these markers in M2 in the absence of Tg, or in M1, treated or not with Tg. |
| Animal experiment [2]: | |
Animal models | Female BALB/c mice |
Preparation Method | 5×104 4T1 cells were injected into immunocompetent 7-week-old female BALB/c mice. Mice bearing 4T1 tumors were treated with PU-WS13 (15mg/kg, i.p.) every day from day 11 post tumor implantation. Mice were sacrificed 24 h after one dose (day 12), five doses (day 15), or 11 doses (day 22) of PU-WS13. Tumors were collected and frozen at −80°C. After thawing, tumors were homogenized in PBS before being crushed. PU-WS13 was extracted in acetonitrile, and the organic layer separated and dried under vacuum. Samples were reconstituted in mobile phase. Concentrations of PU-WS13 in tumors were determined by high-performance LC-MS/MS. PU-H71 was added as the internal standard. |
Dosage form | 15mg/kg; i.p. |
Applications | Inhibition of GRP94 by PU-WS13 limits tumor growth and collagen content and increases CD8+ cells in the tumor microenvironment (TME). |
References: [1]Chaumonnot K, Masson S, Sikner H, et al. The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress[J]. Cell death & disease, 2021, 12(1): 114. [2]Bouchard A, Sikner H, Baverel V, et al. The GRP94 inhibitor PU-WS13 decreases M2-like macrophages in murine TNBC tumors: a pharmaco-imaging study with 99mTc-Tilmanocept SPECT[J]. Cells, 2021, 10(12): 3393. | |
| Cas No. | 1454619-14-7 | SDF | |
| Chemical Name | 8-((3,5-dichlorophenyl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine | ||
| Canonical SMILES | CC(NCCCN1C2=NC=NC(N)=C2N=C1SC3=CC(Cl)=CC(Cl)=C3)C | ||
| Formula | C17H20Cl2N6S | M.Wt | 411.35 |
| Löslichkeit | DMF: 30 mg/mL,DMSO: 30 mg/mL,DMSO:PBS(pH7.2) (1:1): 0.5 mg/mL,Ethanol: 25 mg/mL | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.431 mL | 12.1551 mL | 24.3102 mL |
| 5 mM | 0.4862 mL | 2.431 mL | 4.862 mL |
| 10 mM | 0.2431 mL | 1.2155 mL | 2.431 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
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μL
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Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 10 reference(s) in Google Scholar.)
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