HSP27 inhibitor J2
(Synonyms: J2) 目录号 : GC38503
HSP27 inhibitor J2 (J2) is an inhibitor of HSP27, which significantly induces abnormal HSP27 dimer formation and inhibits HSP27 macropolymer production[1-3].
Cas No.:2133499-85-9
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.00%
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| Cell experiment [1]: | |
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Cell lines |
NCI-H460 cells |
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Preparation Method |
Cells were treated with J2 at 10 µM for 12 hr. |
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Reaction Conditions |
10 µM J2;12 hr |
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Applications |
J2 showed stronger HSP27 cross linking activity in HSP27 high expressed lung cancer cells. |
| Animal experiment [2]: | |
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Animal models |
Male C57BL/6 mice |
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Preparation Method |
Mice were exposed to a single dose of 75 Gy delivered to the left lung in a single fraction,15 mg/kg of J2 was intraperitoneal administered on every other day after irradiation. |
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Dosage form |
15 mg/kg; i.p; every other day after irradiation for 14d. |
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Applications |
J2 treatment significantly inhibited immune cell infiltration in lung tissue. |
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References: [1]. Choi B, Choi SK, et,al. Sensitization of lung cancer cells by altered dimerization of HSP27. Oncotarget. 2017 Oct 31;8(62):105372-105382. doi: 10.18632/oncotarget.22192. PMID: 29285257; PMCID: PMC5739644. |
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HSP27 inhibitor J2 (J2) is an inhibitor of HSP27, which significantly induces abnormal HSP27 dimer formation and inhibits HSP27 macropolymer production[1-3].
J2(10 µM J2;12 hr)showed stronger HSP27 cross linking activity in HSP27 high expressed lung cancer cells and relatively low cytoxicity[4].
J2(15 mg/kg; i.p; on every other day after irradiation for 14d) treatment significantly inhibited immune cell infiltration in lung tissue. J2-treated mice reversed radiation-induced respiratory distress. J2 inhibited IR-induced lung fibrosis in mice[5-6].
HSP27抑制剂J2 (J2)是HSP27的抑制剂,能显著诱导异常HSP27二聚体形成,抑制HSP27大聚合物的生成[1-3]。
J2在高表达HSP27的肺癌细胞中表现出较强的HSP27交联活性,并且细胞毒性相对较低[4]。
J2(15 mg/kg; i.p; on every other day after irradiation for 14d)显著抑制肺组织免疫细胞浸润。j2治疗小鼠逆转了辐射引起的呼吸窘迫。J2抑制IR诱导的小鼠肺纤维化[5-6]。
References:
[1]. Hwang SY, Kwak SY, et,al. Synthesis and biological effect of chrom-4-one derivatives as functional inhibitors of heat shock protein 27. Eur J Med Chem. 2017 Oct 20;139:892-900. doi: 10.1016/j.ejmech.2017.08.065. Epub 2017 Sep 1. PMID: 28869891.
[2]. Garrido C, Bruey JM, et,al. HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J. 1999 Nov;13(14):2061-70. doi: 10.1096/fasebj.13.14.2061. PMID: 10544189.
[3]. Younghwa Na, et al. Methods for treating pulmonary fibrosis using chromenone derivatives.
[4]. Choi B, Choi SK, et,al. Sensitization of lung cancer cells by altered dimerization of HSP27. Oncotarget. 2017 Oct 31;8(62):105372-105382. doi: 10.18632/oncotarget.22192. PMID: 29285257; PMCID: PMC5739644.
[5]. Kim JY, An YM, et,al. HSP27 inhibitor attenuates radiation-induced pulmonary inflammation. Sci Rep. 2018 Mar 8;8(1):4189. doi: 10.1038/s41598-018-22635-9. PMID: 29520071; PMCID: PMC5843649.
[6]. Kim JY, Jeon S, et,al. The Hsp27-Mediated IkBα-NFκB Signaling Axis Promotes Radiation-Induced Lung Fibrosis. Clin Cancer Res. 2019 Sep 1;25(17):5364-5375. doi: 10.1158/1078-0432.CCR-18-3900. Epub 2019 May 24. PMID: 31126962.
| Cas No. | 2133499-85-9 | SDF | |
| 别名 | J2 | ||
| Canonical SMILES | O=C1C=C(C)OC2=C1C(O)=CC(OCC3SC3)=C2 | ||
| 分子式 | C13H12O4S | 分子量 | 264.3 |
| 溶解度 | DMSO: 25 mg/mL (94.59 mM) | 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.7836 mL | 18.9179 mL | 37.8358 mL |
| 5 mM | 0.7567 mL | 3.7836 mL | 7.5672 mL |
| 10 mM | 0.3784 mL | 1.8918 mL | 3.7836 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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HSP27 inhibitor attenuates radiation-induced pulmonary inflammation
Sci Rep 2018 Mar 8;8(1):4189.PMID:29520071DOI:10.1038/s41598-018-22635-9.
Radiation therapy has been used to treat over 70% of thoracic cancer; however, the method usually causes radiation pneumonitis. In the current study, we investigated the radioprotective effects of HSP27 inhibitor (J2) on radiation-induced lung inflammation in comparison to amifostine. In gross and histological findings, J2 treatment significantly inhibited immune cell infiltration in lung tissue, revealing anti-inflammatory potential of J2. Normal lung volume, evaluated by micro-CT analysis, in J2-treated mice was higher compared to that in irradiated mice. J2-treated mice reversed radiation-induced respiratory distress. However, amifostine did not show significant radioprotective effects in comparison to that of J2. In HSP27 transgenic mice, we observed increased immune cells recruitment and decreased volume of normal lung compared to wild type mice. Increased ROS production and oxidative stress after IR were down-regulated by J2 treatment, demonstrating antioxidant property of J2. The entire data of this study collectively showed that J2 may be an effective therapeutic agent for radiation-induced lung injury.
Drug-Like Small Molecule HSP27 Functional Inhibitor Sensitizes Lung Cancer Cells to Gefitinib or Cisplatin by Inducing Altered Cross-Linked Hsp27 Dimers
Pharmaceutics 2021 Apr 28;13(5):630.PMID:33925114DOI:10.3390/pharmaceutics13050630.
Relationships between heat shock protein 27 (HSP27) and cancer aggressiveness, metastasis, drug resistance, and poor patient outcomes in various cancer types including non-small cell lung cancer (NSCLC) were reported, and inhibition of HSP27 expression is suggested to be a possible strategy for cancer therapy. Unlike HSP90 or HSP70, HSP27 does not have an ATP-binding pocket, and no effective HSP27 inhibitors have been identified. Previously, NSCLC cancer cells were sensitized to radiation and chemotherapy when co-treated with small molecule HSP27 functional inhibitors such as zerumbone (ZER), SW15, and J2 that can induce abnormal cross-linked HSP27 dimer. In this study, cancer inhibition effects of NA49, a chromenone compound with better solubility, longer circulation time, and less toxicity than J2, were examined in combination with anticancer drugs such as cisplatin and gefitinib in NSCLC cell lines. When the cytotoxic drug cisplatin was treated in combination with NA49 in epidermal growth factor receptors (EGFRs) WT cell lines, sensitization was induced in an HSP27 expression-dependent manner. With gefitinib treatment, NA49 showed increased combination effects in both EGFR WT and Mut cell lines, also with HSP27 expression-dependent patterns. Moreover, NA49 induced sensitization in EGFR Mut cells with a secondary mutation of T790M when combined with gefitinib. Augmented tumor growth inhibition was shown with the combination of cisplatin or gefitinib and NA49 in nude mouse xenograft models. These results suggest the combination of HSP27 inhibitor NA49 and anticancer agents as a candidate for overcoming HSP27-mediated drug resistance in NSCLC patients.
The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis
J Biomed Sci 2023 Jan 7;30(1):2.PMID:36611161DOI:10.1186/s12929-023-00896-5.
Background: Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods: We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. Results: HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Conclusions: Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.
Sensitization of lung cancer cells by altered dimerization of HSP27
Oncotarget 2017 Oct 31;8(62):105372-105382.PMID:29285257DOI:10.18632/oncotarget.22192.
Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells.
Activation of the HSP27-AKT axis contributes to gefitinib resistance in non-small cell lung cancer cells independent of EGFR mutations
Cell Oncol (Dordr) 2022 Oct;45(5):913-930.PMID:35931945DOI:10.1007/s13402-022-00696-3.
Purpose: Although epidermal growth factor receptor (EGFR)-activating mutations in non-small cell lung cancer (NSCLC) usually show sensitivity to first-generation EGFR-tyrosine kinase inhibitors (TKIs), most patients relapse because of drug resistance. Heat shock protein 27 (HSP27) has been reported to be involved in the resistance of EGFR-TKIs, although the underlying mechanism is unclear. Here, we explore the mechanisms of HSP27-mediated EGFR TKI resistance and propose novel therapeutic strategies. Methods: To determine the mechanism of HSP27 associated gefitinib resistance, differences were assessed using gefitinib-sensitive and -resistant NSCLC cell lines. In vivo xenograft experiments were conducted to elucidate the combinatorial effects of J2, a small molecule HSP27 inhibitor, and gefitinib. Analyses of human NSCLC tissues and PDX tissues were also used for comparison of HSP27 and phosphorylated AKT expression. Results: Large-scale cohort analysis of NSCLC cases revealed that HSP27 expression correlated well with the incidence of EGFR mutations and affected patient survival. Increased pAKT and HSP27 was observed in gefitinib-resistant cells compared with gefitinib-sensitive cells. Moreover, increased phosphorylation of HSP27 by gefitinib augmented its protein stability and potentiated its binding activity with pAKT, which resulted in increased gefitinib resistance. However, in gefitinib-sensitive cells, stronger binding activity between EGFR and HSP27 was observed. Moreover, these phenomena occurred regardless of EGFR mutation including secondary mutations, such as T790M. AKT knockdown switched HSP27-pAKT binding to HSP27-EGFR, which promoted gefitinib sensitivity in gefitinib-resistant cells. Functional inhibition of HSP27 yielded sensitization to gefitinib in gefitinib-resistant cells by inhibiting the interaction between HSP27 and pAKT. Conclusions: Our results indicate that combination of EGFR-TKIs with HSP27 inhibitors may represent a good strategy to overcome resistance to EGFR-TKIs, especially in cancers exhibiting AKT pathway activation.