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.NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. Ewing's sarcoma cells were generally found to be more sensitive to the effects of this compound compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of this neoplasm to IGF-IR signaling. NVP-AEW541 induced a G1 cell cycle block in all cells tested, whereas apoptosis was observed only in those cells that show a high level of sensitivity. NVP-AEW541 represents a class of selective, small molecule IGF-IR kinase inhibitors with proven in vivo antitumor activity and potential therapeutic application.
|Source||PLoS One (2017). Figure 2. NVP-AEW541|
|Cell Lines||MDA-MB-231 and BT-549 cells|
|Incubation Time||24 h|
|Results||Both NVP-AEW541 (1 μM) and rapamycin (10 nM) notably increased the expression level of the autophagy-related protein Beclin-1 and the ratio of LC3-II/LC-I and reduced the level of the selective autophagy substrate p62.|
|Cell lines||MCF-7 cells|
|Preparation method||Seeding between 3 × 103 and 6 × 103 cells/well in 96-well plates with a total media volume of 100 μL/well. Adding increasing concentrations of NVP-AEW541 24 hours thereafter in quadruplicate. After 72 hours , fixing cells by addition of 25 μL/well Glutaraldehyde (20%) and incubation for 10 min at RT. Then washing cells 2× with 200 μL/well H2O and adding 100 μL Methylene Blue (0.05%) . After incubation for 10 min at RT, washing cells 3× with 200 μL/well H2O. adding 200 μL/well HCl (3%) , and following incubation for 30 min at RT on a plate shaker, absorbance is measured at 650 nm.|
|Concentrations||~ 10 μM|
|Incubation time||72 hours|
|Animal models||Female Harlan athymic nude mice weighing 18-25 g with NWT-21 cells|
|Formulation||Dissolved in 25 mM L(+)-tartaric acid|
|Dosages||20, 30, or 50 mg/kg|
|Administration||Administered via p.o. twice daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 80 mg/mL|
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.
Ioannou N, et al. BMC Cancer. 2013 Jan 31;13:41. PMID: 23367880.
Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity.
Bao XH, et al. Anticancer Res. 2012 Jul;32(7):2827-34. PMID: 22753744.
Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors.
Scotlandi K, et al. Cancer Res. 2005 May 1;65(9):3868-76. PMID: 15867386.
In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase.
García-Echeverría C, et al. Cancer Cell. 2004 Mar;5(3):231-9. PMID: 15050915.
|Related IGF-1R Products|
Picropodophyllotoxin is an insulin-like growth factor-I (IGF-I) receptor kinase inhibitor.
AG-1024 (Tyrphostin) inhibits IGF-1R autophosphorylation with IC50 of 7 μM, is less potent to IR with IC50 of 57 μM and specifically distinguishes between InsR and IGF-1R (as compared to other tyrphostins).
AXL1717 (picropodophyllin, Picropodophyllotoxin, PPP) is a non-competitive, potent, and specific inhibitor of IGF-1Rα/β with IC50 of 1 nM.
BMS-754807 is an ATP-competitive dual-kinase inhibitor of IGF-1R and IR with IC50s of 1.8 nM and 1.7 nM, respectively.
PQ401 is an insulin growth factor-1 receptor (IGF-1R) inhibitor.
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