NVP-AEW541

NVP-AEW541 is a potent inhibitor of IGF-1R with IC50 of 86 nM, 27-fold greater selectivity for IGF-1R than InsR.

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NVP-AEW541 Chemical Structure

NVP-AEW541 Chemical Structure
Molecular Weight: 439.55

Validation & Quality Control

Customer Reviews(6)

Quality Control & MSDS

IGF-1R inhibitors with Unique Features

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  • Inhibitor in Clinical Trial

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  • Newest IGF-1R Inhibitor

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Product Information

  • Inhibition Profile
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  • Research Area

Product Description

Biological Activity

Description NVP-AEW541 is a potent inhibitor of IGF-1R with IC50 of 86 nM, 27-fold greater selectivity for IGF-1R than InsR.
Targets IGF-1R
IC50 86 nM [1]
In vitro NVP-AEW541 also inhibits InsR, Tek, Flt1 and Flt3 with IC50 of 140 nM, 530 nM, 600 nM and 420 nM in purified kinases/recombinant kinase domains assay. NVP-AEW541 is more selective and shows 27-fold more potent than InsR at the cellular level. NVP-AEW541 suppresses the IGF-I-mediated survival, soft agar and proliferation of MCF-7 cells with IC50 of 0.162 μM, 0.105 μM and 1.64 μM, respectively. NVP-AEW541 also reduces the level of phospho-IGF-1R and phospho-PKB in NWT-21 cells. [1] NVP-AEW541 shows growth inhibitory effect on TC-71 musculoskeletal sarcoma cells in low-serum medium as well as in 10% FBS–containing medium. NVP-AEW541 inhibits cell cycle progression and induces specific G1 arrest in sarcoma cell lines (TC-71, SK-N-MC, SaoS-2, RD/18 and RH4). [2] NVP-AEW541 could inhibit the growth of human neuroblastoma cells with IC50 of 0.4-6.8 μM. An increase in the hypodiploid fraction and the depletion of the S and G2-M compartments could be detected in these cell lines. NVP-AEW541-driven inhibition of IGF-1R causes a reduction of phosphorylation of Akt, but not of Erk1 and Erk2 in neuroblastoma cells. [3] NVP-AEW541 inhibits glioma cell growth and disrupts the autocrine loop initiated by HIF1α stabilization. [4] A recent study shows that NVP-AEW541 suppresses the proliferation and viability of PC3, DU145, and 22Rv1 prostate cancer cells, without necessarity of associated cell death. NVP-AEW541 decreases phospho-Akt levels in 22Rv1 and DU415 cells but not PC3 cells, without affecting total Akt levels, which shows that PTEN status could determine the effectiveness of NVP-AEW541 with essential Akt. NVP-AEW541-induced radiosensization is dependent on Akt activation status. NVP-AEW541 could increase the H2AX phosphorylation (a measure of DSBs) in PC3, DU145, and 22Rv1 cells. [5]
In vivo NVP-AEW541 (50 mg/kg, p.o.) results in abrogation of basal and IGF-I-induced receptor, and PKB and MAPK phosphorylation, with T/C value of 14% in the NWT-21 tumor xenograft. [1] NVP-AEW541 (50 mg/kg) causes tumor shrinkage in both HTLA-230 and SK-N-BE2c xenografts, without signs of systemic toxicity. NVP-AEW541 could inhibit tumor invasion both in Matrigel-coated chambers and in HTLA-230 xenografts. [3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro kinase assays NVP-AEW541 is dissolved in DMSO (10 mM) and stored at -20 °C. Dilutions are freshly made in DMSO/water 1:1. The final concentration of DMSO in the enzyme assays is <0.5 %. The protein kinase assays are carried out in 96-well plates at RT and terminated by the addition of 20 μL of 125 mM EDTA. Subsequently, 30 μL (c-Abl, c-Src, IGF-1R) of the reaction mixture are transferred onto Immobilon-PVDF presoaked for 5 min with methanol, rinsed with water, then soaked for 5 min with 0.5 % H3PO4 and mounted on vacuum manifold. After spotting all samples, vacuum is connected and each well rinsed with 200 μL 0.5 % H3PO4. Membranes are removed and washed 4× on a shaker with 1.0 % H3PO4, once with ethanol. After drying, mounting in Packard TopCount 96-well frame, and adding of 10 μL/well of Microscint, membranes are counted. IC50 values are calculated by linear regression analysis of the percentage inhibition of NVP-AEW541 in duplicate, at four concentrations (usually 0.01, 0.1, 1, and 10 μM). One unit of protein kinase activity is defined as 1 nmol of 33P transferred from [γ33P]ATP to the substrate protein per minute per mg of protein at 37 °C.

Cell Assay: [1]

Cell lines MCF-7 cells
Concentrations ~ 10 μM
Incubation Time 72 hours
Method Between 3 × 103 and 6 × 103 cells/well are seeded in 96-well plates with a total media volume of 100 μL/well. Increasing concentrations of NVP-AEW541 is added 24 hours thereafter in quadruplicate. 72 hours later, cells are fixed by addition of 25 μL/well Glutaraldehyde (20%) and incubation for 10 min at RT. Cells are then washed 2× with 200 μL/well H2O and 100 μL Methylene Blue (0.05%) is added. After incubation for 10 min at RT, cells are washed 3× with 200 μL/well H2O. 200 μL/well HCl (3%) is added, and following incubation for 30 min at RT on a plate shaker, absorbance is measured at 650 nm.

Animal Study: [1]

Animal Models Female Harlan athymic nude mice weighing 18-25 g with NWT-21 cells
Dosages 20, 30, or 50 mg/kg
Administration Administered via p.o. twice daily
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 20 mg/mL
1

References

Chemical Information

Download NVP-AEW541 SDF
Molecular Weight (MW) 439.55
Formula

C27H29N5O

CAS No. 475489-16-8
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Syonnyms N/A
Solubility (25°C) * In vitro DMSO 88 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 20 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 7-((1s,3s)-3-(azetidin-1-ylmethyl)cyclobutyl)-5-(3-(benzyloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Preparing Stock Solutions

Stock Solution (1ml DMSO) 1mM 10mM 20mM 30mM
Mass(mg) 0.43955 4.3955 8.791 13.1865

Research Area

Customer Reviews (6)


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Rating
Source Mol Cancer Ther 2011.April 10:697-707. NVP-AEW541 purchased from Selleck
Method Western blotting/colony formation assay
Cell Lines mouse tumor primary cell
Concentrations 0-5 µmol/L
Incubation Time
Results NVP-AEW541 inhibited tumor cell growth better in the primary cell culture with the higher baseline Igf1r level (IC50 1.5 µmol/L vs. 300 nmol/L for low and high Igf1r expressing cells, respectively; Fig. A). Anchorage-dependent colony formation assays showed that the colony forming ability of the tumor cells was drastically reduced on treatment with 1 mmol/L NVP-AEW541(Fig. B), but again sensitivity was increased for the cell culture with the higher baseline level of Igf1r expression. Similar results were obtained for anchorage-independent soft agar colony formation assays (Fig. C). Biochemical interrogation revealed that phosphorylation of Igf1r and downstream mediators Mapk, Akt, IRS-1, and P70-S6 kinase were inhibited on treatment with NVP-AEW541(Fig. D)

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Rating
Source Clin Cancer Res 2011 April 17:2237-2249. NVP-AEW541 purchased from Selleck
Method Western blot
Cell Lines TC1889 cells
Concentrations 0.5/5 µM
Incubation Time 2 h
Results IGF-1R inhibition with PPP, a IR3, BMS-536924, as well as NVPAEW541 reduced the IGF-I-induced activation of PI3K/Akt and MAPK/Erk signaling. However, inhibitory effects, particularly on Akt phosphorylation (Fig. C), were more marked with NVPAEW541 and BMS-536924 which are both known to also inhibit the insulin receptor. Treatment with the IGF-1R/IR inhibitors NVPAEW541 and BMS-536924 both induced a marked decrease in phsophorylated Akt, which corresponded to their aforementioned strong inhibitory effect on IGF-stimulated Akt signaling. Effects on MAPK/Erk signaling with these compounds were however heterogenous, with BMS-536924 rather decreasing Erk phosphorylation, whereas NVPAEW541 activated Erk (Fig. D).

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Rating
Source J Clin Invest 2011.November 121:4311-21. NVP-AEW541 purchased from Selleck
Method Western blots
Cell Lines SW837/LoVo/HCT-116 cells
Concentrations 1 μM
Incubation Time 6 h
Results

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Rating
Source Mol Cancer Ther 2011.April 10:697-707.. NVP-AEW541 purchased from Selleck
Method Western blot/Quantification of drug response of ARMS cells on the quail CAM/FACS
Cell Lines rhabdomyosarcoma primary cell
Concentrations 0-5 µmol/L
Incubation Time 48 h
Results NVP-AEW541 treatment of mouse primary tumor cell cultures caused cell cycle arrest in G1 phase (Fig. A). The proportion of cells in G1 phase increased from 52.2% in untreated cells to 68.4% cells in G1 phase when cells were treated with 2 µmol/L NVP-AEW541 (P < 0.05). Western blotting showed the presence of cleaved caspase-3 in tumor cells treated with 5 µmol/L NVP-AEW541 but not at lower concentrations (Fig. B). These results indicate that NVP-AEW541 reduces tumor cell growth primarily by causing cell cycle arrest and secondarily by inducing apoptosis in rhabdomyosarcoma. CAM harboring tumor cells treated withNVP-AEW541 showed 87% less growth compared to the DMSO treated tumor cells (P =0.006), which was better than the growth inhibition seen for imatinib (P = 0.039) at the dosages tested (Fig. C and D)

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Rating
Source Mol Cancer Ther 2011.April 10:697-707. NVP-AEW541 purchased from Selleck
Method Cell viability assay
Cell Lines murine rhabdo myosarcom primary cell
Concentrations 5 μmol/L
Incubation Time 72 h
Results The results of the cell viability assay showed that NVP-AEW541 alone led to an unexpected increase in cell growth at moderate doses for the NVP-AEW541 resistant cell culture. However , the cell growth inhibition could be cooperatively improved by addition of lapatinib (cooperativity index 0.1) , although lapatinib alone had no substantial effect on naive or resistant tumor cells (Fig. A and B). To examine the activity of Igf1r a nd Her2 in NVP-AEW 541 resistant primary tumor cell lines, Resistant cell cultures treated with lapatinib showed decreased p-Her2 levels; however, no difference in Her2 activity was observed in cells treated with NVP-AEW541. When the resistant cells were treated with lapatinib, a surprising increase in the levels of p-Igf1r was observed in comparison vehicle treated cells (Fig. C)

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Rating
Source Clin Cancer Res 2011 April 17:2237-2249. NVP-AEW541 purchased from Selleck
Method MTT-assays
Cell Lines TC1889 cells
Concentrations 0-10 µM
Incubation Time 48/72 h
Results We additionally analyzed the effects of a neutralizing IGF-1R antibody (αIR3) and of the IGF-1R inhibitors NVP-AEW541 (NVP) and BMS-536924 (BMS). Notably, all of these strategies to interfere with IGF-1R signaling reduced TC1889 cell viability and significantly induced apoptosis.

Product Citations (10)

Tech Support & FAQs

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