NVP-AEW541IGF-IR inhibitor, novel, potent and selective CAS# 475489-16-8 |
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Quality Control & MSDS
3D structure
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| Cas No. | 475489-16-8 | SDF | Download SDF |
| PubChem ID | 11476171 | Appearance | Powder |
| Formula | C27H29N5O | M.Wt | 439.55 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | AEW541 | ||
| Solubility | DMSO : ≥ 51 mg/mL (116.03 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 7-[3-(azetidin-1-ylmethyl)cyclobutyl]-5-(3-phenylmethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine | ||
| SMILES | C1CN(C1)CC2CC(C2)N3C=C(C4=C3N=CN=C4N)C5=CC(=CC=C5)OCC6=CC=CC=C6 | ||
| Standard InChIKey | AECDBHGVIIRMOI-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C27H29N5O/c28-26-25-24(21-8-4-9-23(14-21)33-17-19-6-2-1-3-7-19)16-32(27(25)30-18-29-26)22-12-20(13-22)15-31-10-5-11-31/h1-4,6-9,14,16,18,20,22H,5,10-13,15,17H2,(H2,28,29,30) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | NVP-AEW541 is a novel, potent and selective inhibitor of IGF-IR kinase with IC50 value of 0.086 μM. | |||||
| Targets | IGF-IR kinase | |||||
| IC50 | 0.086 μM | |||||
| Kinase experiment [1]: | |
| Inhibitory activities | The baculovirus expressing the amino acid region 950-1337 of the mature cytoplasmic domain of the human IGF-IR was generated as a GST fusion protein. Tyrosine protein kinase assays with purified GST-IGF-IR (100 ng) were performed in a final volume of 30 μl containing 20 mM Tris-HCl (pH 7.6), 10 mM MgCl2, 0.01 mM Na3VO4, 1 % DMSO, 1 mM DTT, and 30 μM (IGF-IR) of poly(Glu,Tyr) 4:1, and 0.1 μCi ATP (γ-[33P]-ATP). The assay was carried out for 20 min at RT. The activities of protein kinases were assayed in the presence of NVP-AEW541 by measuring the incorporation of 33P from [33P]ATP into appropriate substrates. NVP-AEW541 was dissolved in DMSO (10 mM) and stored at -20℃. Dilutions were freshly made in DMSO/water 1:1. The final concentration of DMSO in the enzyme assays was <0.5 %. The protein kinase assays were carried out in 96-well plates for 20 min at RT and terminated by the addition of 20 μl of 125 mM EDTA. |
| Cell experiment [1]: | |
| Cell lines | NWT-21 cells; MCF-7 cells |
| Preparation method | The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
| Reacting condition | Cellular autophosphorylation assays: 90 min.Proliferation assay: 48 h. |
| Applications | NVP-AEW541 inhibits IGF-IR kinase autophosphorylation with IC50 value of 0.086 μM and exhibits 27-fold more potent toward the native IGF-IR. Also, NVP-AEW541 inhibits IGF-I-mediated survival of MCF-7 cells and inhibits IGF-IR-mediated signaling. |
| Animal experiment [1]: | |
| Animal models | Female Harlan athymic nude mice bearing NWT-21 fibrosarcoma tumor model |
| Dosage form | P.o. twice daily, 7 days/week with NVP-AEW541 (20, 30, or 50 mg/kg) |
| Preparation method | 10 ml/kg dissolved in 25 mM L(+)-tartaric acid |
| Application | NVP-AEW541 dose-dependently inhibits tumor growth with T/C (mean increase of tumor volumes of treated animals divided by the mean increase of tumor volumes of control animals multiplied by 100) values of 32%, 28% and 14% in 20 mg/kg, 30 mg/kg, or 50 mg/kg, respectively. NVP-AEW541 is well tolerated at the doses applied, and the recorded variations in body weight are not statistically significant. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: [1]. García-Echeverría C, Pearson MA, Marti A, et al. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell, 2004, 5(3): 231-239. | |
NVP-AEW541 Dilution Calculator
NVP-AEW541 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2751 mL | 11.3753 mL | 22.7505 mL | 45.5011 mL | 56.8764 mL |
| 5 mM | 0.455 mL | 2.2751 mL | 4.5501 mL | 9.1002 mL | 11.3753 mL |
| 10 mM | 0.2275 mL | 1.1375 mL | 2.2751 mL | 4.5501 mL | 5.6876 mL |
| 50 mM | 0.0455 mL | 0.2275 mL | 0.455 mL | 0.91 mL | 1.1375 mL |
| 100 mM | 0.0228 mL | 0.1138 mL | 0.2275 mL | 0.455 mL | 0.5688 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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NVP-AEW541 is a novel, potent and selective inhibitor of IGF-IR kinase with IC50 value of 0.086 ?M [1].
NVP-AEW541 is a pyrrolo(2,3-d) pyrimidine derivative. It has been reported to abolish IGF-I-induced IGF-IR autophosphorylation and to block the IGF-IR signaling pathway mainly in ECC-1 and USPC-1 cancer cells. Also in these cell lines, NVP-AEW541 has been shown to change the IGF-I induced cell cycle and to lead apoptotic cell death as well as exhibit antiproliferative effects [2]. In addition, it is observed that NVP-AEW541 can induce radiosensitization in PTEN wild-type cell lines [3].
References:
[1] Carlos Garc?a-Echeverr?a, Mark A. Pearson, Andreas Marti, Thomas Meyer, Juergen Mestan, Johann Zimmermann, Jiaping Gao, Josef Brueggen, Hans-Georg Capraro, Robert Cozens, Dean B. Evans, Doriano Fabbro, Pascal Furet, Diana Graus Porta, Janis Liebetanz, Georg Martiny-Baron, Stephan Ruetz, and Francesco Hofmann. In vivo antitumor activity of NVP-AEW541—A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell.2004 Mar (5):231-239.
[2] Zohar Attias-Geva, Itay Bentov, Ami Fishman, Haim Werner, Ilan Bruchim. Insulin-like growth factor-I receptor inhibition by speci?c tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines. Gynecologic Oncology. 2011 Feb (121):383-389.
[3] Sofie F. Isebaert, Johannes V. Swinnen, William H. Mcbride, and Karin M. Haustermans. Insulin-like growth factor–type 1 receptor inhibitor NVP-AEW541 enhances radiosensitivity of PTEN wild-type but not PTEN-deficient human prostate cancer cells. International Journal of Radiation Oncology Biology Physics. 2011 (81):239-247.
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Treatment with a combination of the ErbB (HER) family blocker afatinib and the IGF-IR inhibitor, NVP-AEW541 induces synergistic growth inhibition of human pancreatic cancer cells.[Pubmed:23367880]
BMC Cancer. 2013 Jan 31;13:41.
BACKGROUND: Aberrant expression and activation of the IGF-IR have been reported in a variety of human cancers and have been associated with resistance to HER targeted therapy. In this study, we investigated the effect of simultaneous targeting of IGF-IR and HER (erbB) family, with NVP-AEW541 and afatinib, on proliferation of pancreatic cancer cells. METHODS: The sensitivity of a panel of human pancreatic cancer cell lines to treatment with NVP-AEW541 used alone or in combination with afatinib, anti-EGFR antibody ICR62, and cytotoxic agents was determined using the Sulforhodamine B colorimetric assay. Growth factor receptor expression, cell-cycle distribution and cell signalling were determined using flow cytometry and western blot analysis. RESULTS: All pancreatic cancer cell lines were found to be IGF-IR positive and NVP-AEW541 treatment inhibited the growth of the pancreatic cancer cell lines with IC50 values ranging from 342 nM (FA6) to 2.73 muM (PT45). Interestingly, of the various combinations examined, treatment with a combination of NVP-AEW541 and afatinib was superior in inducing synergistic growth inhibition of the majority of pancreatic cancer cells. CONCLUSION: Our results indicate that co-targeting of the erbB (HER) family and IGF-IR, with a combination of afatinib and NVP-AEW541, is superior to treatment with a single agent and encourages further investigation in vivo on their therapeutic potential in IGF-IR and HER positive pancreatic cancers.
Insulin-like growth factor-type 1 receptor inhibitor NVP-AEW541 enhances radiosensitivity of PTEN wild-type but not PTEN-deficient human prostate cancer cells.[Pubmed:21816290]
Int J Radiat Oncol Biol Phys. 2011 Sep 1;81(1):239-47.
PURPOSE: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells. METHODS AND MATERIALS: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt. RESULTS: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt. CONCLUSIONS: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.
Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity.[Pubmed:22753744]
Anticancer Res. 2012 Jul;32(7):2827-34.
AIM: To assess the effects of a novel type 1 insulin-like growth factor receptor (IGF-1R) inhibitor, NVP-AEW541, on cell proliferation and signal transduction of esophageal cancer. MATERIALS AND METHODS: Cell proliferation assay and western blot were conducted to assess the antitumor effects of NVP-AEW541. Genetic modification of RAS by expression vector was applied for overexpression of mutant RAS. RESULTS: More than 2 mumol/l of NVP-AEW541 was required to effectively inhibit the proliferation of esophageal cancer. NVP-AEW541 potently blocked the activation of IGF-1R and protein kinase B (PKB, also known as AKT), but not of mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinases (ERK). Active RAS was not reduced by NVP-AEW541 in esophageal cancer cells TE-1, suggesting that insensitivity of esophageal cancer to NVP-AEW541 is due to the maintained RAS-MAPK activity, which did not arise from RAS mutation. Moreover, the transduction of mutant RAS reduced the sensitivity of TE-1 cells to NVP-AEW541. CONCLUSION: Stimulation of RAS-MAPK pathway is associated with resistance to NVP-AEW541 in esophageal cancer. Combining NVP-AEW541 with inhibitors/antibodies against RAS-MAPK signaling molecules might be more effective for use against esophageal cancer.
Co-Targeting IGF-1R and Autophagy Enhances the Effects of Cell Growth Suppression and Apoptosis Induced by the IGF-1R Inhibitor NVP-AEW541 in Triple-Negative Breast Cancer Cells.[Pubmed:28046018]
PLoS One. 2017 Jan 3;12(1):e0169229.
BACKGROUND: Triple-negative breast cancer (TNBC) is the most intractable type of breast cancer, and there is a lack of effective targeted therapy. Insulin-like growth factor-1 receptor (IGF-1R) is reportedly a potential target for TNBC treatment. However, satisfying treatment outcomes in breast cancer patients have yet to be achieved with IGF-1R-targeted agents. METHODS: To confirm whether inhibiting IGF-1R could induce autophagy, we detected autophagy-related proteins by western blotting and immunofluorescence staining of LC3-II. The IGF-1R inhibitor NVP-AEW541, autophagy inhibitor 3-methyladenine (3-MA) and Atg7 small interfering RNA (siRNA) were used to further investigate the effects of autophagy induced by IGF-1R inhibition in TNBC cells. The CCK8 assay, EdU assay, apoptosis and cell cycle analyses were applied to test cell function after treatment. RESULTS: NVP-AEW541 markedly induced autophagy in TNBC cells by increasing the levels of the autophagy-related protein Beclin-1 and the LC3-II/LC-I ratio and reducing the selective autophagy substrate p62. Joint application of 3-MA or Atg7 siRNA enhanced the cell growth inhibition and apoptosis effects of NVP-AEW541 by arresting cells at G1/G0 phase and increasing Bax expression and decreasing that of Bcl-2. CONCLUSION: Targeting IGF-1R in TNBC induces cell-protective autophagy, thereby weakening the therapeutic effect of agents directed toward IGF-1R. Our findings reveal that combined use autophagy-disrupting agents can enhance the therapeutic efficacy of IGF-1R inhibitors in TNBC cells and may provide a valuable treatment strategy for IGF-1R inhibitor-based therapies for TNBC and other IGF-1 signaling-associated tumors.
