NSC305787
目录号 : GC33091
NSC305787 是一种 ezrin 抑制剂，Kd 为 5.85 μM，抑制由 PKC&Iota 引起的 ezrin 磷酸化； IC50 为 8.3 μM，具有抗肿瘤活性。
Cas No.:785718-37-8
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: | Human umbilical vein endothelial cells (HUVECs; 2.5 × 104/well) are seeded in a 96-well plate in endothelial growth media-2. Following formation of a confluent HUVEC monolayer (∼32 h), endothelial growth media-2 is aspirated and a layer of osteosarcoma (OS) cells (1.0 × 104 cells/well) is added to Dulbecco’s modified Eagle medium containing NSC305787. This specific time point is accepted as 0 h of treatment, and invasion is monitored during the subsequent 5 h by measuring changes in resistance at the cell-electrode interphase. The cell index is calculated according to the following formula: cell index = (Rt – R0)/F, where Rt is resistance at time point t, R0 is background resistance (measured with media alone, no cells) and F is frequency at which the measurement is taken (10 kHz)[1]. |
Animal experiment: | Mice[2]The Osx-Cre+p53fl/flpRBfl/fl transgenic mouse model of osteosarcoma is used in the assay. Mice are treated with 240 μg/kg/day NSC305787, 226 μg/kg/day NSC668394, or vehicle (DMSO, 1%) once daily, five times a week by i.p. injection in a volume of 100 μL. At the end of the study, lung and tumor samples are isolated upon necropsy. Half of each sample is flash frozen immediately in liquid nitrogen, and the other half is fixed in 10% formalin for 18-24 h, transferred to 70% ethanol, and stored at room temperature[2]. |
References: [1]. Bulut G, et al. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene. 2012 Jan 19;31(3):269-81. | |
NSC305787 is an inhibitor of ezrin with a Kd of 5.85 μM, inhibits the phosphorylation of ezrin caused by PKCΙ with an IC50 of 8.3 μM, has antitumor activity.
NSC305787 is an inhibitor of ezrin with a Kd of 5.85 μM, and has antitumor activity. NSC305787 inhibits PKCΙ phosphorylation of Ezrin, Moesin, Radixin, MBP, with IC50s of 8.3, 9.4, 55, 58.9 μM, respectively. NSC305787 binds to PKCΙ with a Kd value of 172.4 μM, and inhibits ezrin T567 phosphorylation primarily via its binding to ezrin and not through inhibition of PKCΙ kinase activity. NSC305787 (1, 10 μM) shows inhibitory activity against ezrin-mediated invasion of K7M2 osteosarcoma (OS) cells. Moreover, NSC305787 (10 μM) reduces cell motility phenotypes in zebrafish and blocks OS metastatic growth in lung organ culture[1].
NSC305787 (0.240 mg/kg/day, i.p.) suppresses ezrin-dependent osteosarcoma metastatic growth in mouse lung[1]. NSC305787 (240 μg/kg, i.p.) dramatically inhibits pulmonary metastasis in a transgenic mouse model of osteosarcoma (Osx-Cre+p53fl/flpRBfl/fl) and shows a more favorable pharmacokinetic profile compared with NSC668394 in the mouse model[2].
[1]. Bulut G, et al. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene. 2012 Jan 19;31(3):269-81. [2]. ?elik H, et al. Ezrin Inhibition Up-regulates Stress Response Gene Expression. J Biol Chem. 2016 Jun 17;291(25):13257-70.
| Cas No. | 785718-37-8 | SDF | |
| Canonical SMILES | OC(C1NCCCC1)C2=CC(C3(C4)CC5CC4CC(C5)C3)=NC6=C(Cl)C=C(Cl)C=C26 | ||
| 分子式 | C25H30Cl2N2O | 分子量 | 445.42 |
| 溶解度 | DMSO : 6 mg/mL (13.47 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 | 2.2451 mL | 11.2254 mL | 22.4507 mL |
| 5 mM | 0.449 mL | 2.2451 mL | 4.4901 mL |
| 10 mM | 0.2245 mL | 1.1225 mL | 2.2451 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells
Invest New Drugs 2022 Aug;40(4):728-737.PMID:35477813DOI:10.1007/s10637-022-01249-z.
Pancreatic cancer is one of the most lethal human neoplasms, and despite advances in the understanding of the molecular complexity involved in the development and progression of this disease, little of this new information has been translated into improvements in therapy and prognosis. Ezrin (EZR) is a protein that regulates multiple cellular functions, including cell proliferation, survival, morphogenesis, adhesion, and motility. In pancreatic cancer, EZR is highly expressed and reflects an unfavorable prognosis, whereas EZR silencing ameliorates the malignant phenotype of pancreatic cancer cells. NSC305787 was identified as a pharmacological EZR inhibitor with favorable pharmacokinetics and antineoplastic activity. Here, we endeavored to investigate the impact of EZR expression on survival outcomes and its associations with molecular and biological characteristics in The Cancer Genome Atlas pancreatic adenocarcinoma cohort. We also assessed the potential antineoplastic effects of NSC305787 in pancreatic cancer cell lines. High EZR expression was an independent predictor of worse survival outcomes. Functional genomics analysis indicated that EZR contributes to multiple cancer-related pathways, including PI3K/AKT/mTOR signaling, NOTCH signaling, estrogen-mediated signaling, and apoptosis. In pancreatic cells, NSC305787 reduced cell viability, clonal growth, and migration. Our exploratory molecular studies identified that NSC305787 modulates the expression and activation of key regulators of the cell cycle, proliferation, DNA damage, and apoptosis, favoring a tumor-suppressive molecular network. In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer.
Ezrin is highly expressed and a druggable target in chronic lymphocytic leukemia
Life Sci 2022 Dec 15;311(Pt B):121146.PMID:36336127DOI:10.1016/j.lfs.2022.121146.
Aims: Despite the development of therapeutic strategies for chronic lymphocytic leukemia (CLL), most patients remain incurable, relapse, or refractory to current treatments, indicating the need to expand the antineoplastic repertoire for this disease. Ezrin (EZR) is a known oncogene in solid tumors and plays a key role in cell survival and BCR-mediated signaling activation in B-cell lymphomas. However, its role in hematological neoplasms remains poorly explored. Main methods: The present study assessed EZR expression in samples from CLL patients and healthy donors and evaluated the cellular and molecular effects of a pharmacological EZR inhibitor, NSC305787, in CLL cellular models. Key findings: EZR was highly expressed and positively associated with relevant signaling pathways related to CLL development and progression, including TP53, PI3K/AKT/mTOR, NF-κB, and MAPK. NSC305787 reduced viability, clonogenicity, and cell cycle progression and induced apoptosis in CLL cells. Pharmacological EZR inhibition also attenuated ERK, S6RP, and NF-κB activation, indicating that EZR not only associates with but also activates these signaling pathways in CLL. Ex vivo assays revealed that the EZR inhibition-induced cell viability reduction was independent of molecular risk and the Binet stage. Significance: Our study provides insights into EZR as a pharmacological target in CLL, shedding light on a novel strategy for treating this disease.
Ezrin Inhibition Up-regulates Stress Response Gene Expression
J Biol Chem 2016 Jun 17;291(25):13257-70.PMID:27137931DOI:10.1074/jbc.M116.718189.
Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes.
Ezrin Binds to DEAD-Box RNA Helicase DDX3 and Regulates Its Function and Protein Level
Mol Cell Biol 2015 Sep;35(18):3145-62.PMID:26149384DOI:10.1128/MCB.00332-15.
Ezrin is a key regulator of cancer metastasis that links the extracellular matrix to the actin cytoskeleton and regulates cell morphology and motility. We discovered a small-molecule inhibitor, NSC305787, that directly binds to ezrin and inhibits its function. In this study, we used a nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS-MS)-based proteomic approach to identify ezrin-interacting proteins that are competed away by NSC305787. A large number of the proteins that interact with ezrin were implicated in protein translation and stress granule dynamics. We validated direct interaction between ezrin and the RNA helicase DDX3, and NSC305787 blocked this interaction. Downregulation or long-term pharmacological inhibition of ezrin led to reduced DDX3 protein levels without changes in DDX3 mRNA. Ectopic overexpression of ezrin in low-ezrin-expressing osteosarcoma cells caused a notable increase in DDX3 protein levels. Ezrin inhibited the RNA helicase activity of DDX3 but increased its ATPase activity. Our data suggest that ezrin controls the translation of mRNAs preferentially with a structured 5' untranslated region, at least in part, by sustaining the protein level of DDX3 and/or regulating its function. Therefore, our findings suggest a novel function for ezrin in regulation of gene translation that is distinct from its canonical role as a cytoskeletal scaffold at the cell membrane.
Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells
Oncogene 2012 Jan 19;31(3):269-81.PMID:21706056DOI:10.1038/onc.2011.245.
Ezrin is a multifunctional protein that connects the actin cytoskeleton to the extracellular matrix through transmembrane proteins. High ezrin expression is associated with lung metastasis and poor survival in cancer. We screened small molecule libraries for compounds that directly interact with ezrin protein using surface plasmon resonance to identify lead compounds. The secondary functional assays used for lead compound selection included ezrin phosphorylation as measured by immunoprecipitation and in vitro kinase assays, actin binding, chemotaxis, invasion into an endothelial cell monolayer, zebrafish and Xenopus embryonic development, mouse lung organ culture and an in vivo lung metastasis model. Two molecules, NSC305787 and NSC668394, that directly bind to ezrin with low micromolar affinity were selected based on inhibition of ezrin function in multiple assays. They inhibited ezrin phosphorylation, ezrin-actin interaction and ezrin-mediated motility of osteosarcoma (OS) cells in culture. NSC305787 mimicked the ezrin morpholino phenotype, and NSC668394 caused a unique developmental defect consistent with reduced cell motility in zebrafish. Following tail vein injection of OS cells into mice, both molecules inhibited lung metastasis of ezrin-sensitive cells, but not ezrin-resistant cells. The small molecule inhibitors NSC305787 and NSC668394 demonstrate a novel targeted therapy that directly inhibits ezrin protein as an approach to prevent tumor metastasis.