PU-WS13
目录号 : GC13307
PU-WS13是一种嘌呤支架类Grp94特异性热休克蛋白90（Hsp90）抑制剂。
Cas No.:1454619-14-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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. | |
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.
PU-WS13是一种嘌呤支架类Grp94特异性热休克蛋白90（Hsp90）抑制剂[1]。在人类中，细胞质中的Hsp90α和Hsp90β、内质网中的Grp94和线粒体中的Trap-1是四种Hsp90旁系同源物[2]。PU-WS13的作用机制是通过占据Grp94中的ATP位点来阻断Grp94与IgG复合物的形成[3]。
在体外，PU-WS13（25μM）处理M2巨噬细胞72h，阻止了毒胡萝卜素（Tg）诱导的Grp94分泌，减弱了内质网（ER）应激，减少了促炎因子IFNγ、IL-6和TNFα的分泌，减少了细胞内组织蛋白酶L[4]。PU-WS13（50μM）处理表达FLT3-ITD的MV4-11细胞24h，显著降低了细胞的存活率，诱导了细胞膜易位[5]。
在体内，PU-WS13（15mg/kg）通过腹腔注射处理野生型小鼠，抑制了Grp94从而限制肿瘤生长和胶原蛋白含量，并增加了肿瘤微环境（TME）中的CD8+细胞数量[6]。PU-WS13（20mg/kg）通过气管内治疗甲流病毒和肺炎链球菌共感染的小鼠，显著减少了肺部细菌定植，改善了肺部病理学，恢复了肺组织中E-钙粘蛋白的表达[7]。
| Cas No. | 1454619-14-7 | SDF | |
| 化学名 | 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 | ||
| 分子式 | C17H20Cl2N6S | 分子量 | 411.35 |
| 溶解度 | DMF: 30 mg/mL,DMSO: 30 mg/mL,DMSO:PBS(pH7.2) (1:1): 0.5 mg/mL,Ethanol: 25 mg/mL | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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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 |
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