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 |
| Method | western blotting | |
| Cell Lines | MDA-MB-231 and BT-549 cells | |
| Concentrations | 1 μM | |
| 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 Experiment | |
|---|---|
| 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 Experiment | |
|---|---|
| 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 |
| Molecular Weight | 439.55 |
| Formula | C27H29N5O |
| CAS Number | 475489-16-8 |
| Solubility (25°C) | DMSO 45 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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|---|
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IGF-I (24-41) (Insulin-like Growth Factor I (24-41)) is amino acids 24 to 41 fragment of IGF-I. |
| GIP, human
GIP, human is a peptide hormone consisting of 42 amino acids that also acts as a promoter of glucose-dependent insulin secretion and a weak inhibitor of gastric acid secretion. In addition, GIP, human acts as an enteric proinsulin hormone released by intestinal K cells in response to nutrient intake. |
| VMB-100
VMB-100 is an engineered mRNA molecule encoding human insulin-like growth factor-1 (IGF-1) that induces IGF-1 expression in human muscle cells. |
| NBI-31772 hydrate
NBI-31772 hydrate is a potent inhibitor of interaction between insulin-like growth factor (IGF) and IGF-binding proteins (IGFBPs). NBI-31772 hydrate is also a nonpeptide ligand that releases bioactive IGF-I from the IGF-I/IGFBP-3 complex (Kis=1-24 nM for all six human subtypes). Anxiolytic and antidepressant-like effects. |
| AZ12253801
AZ12253801 is an ATP-competitive IGF-1R tyrosine kinase inhibitor that shows ∼10-fold selectivity over the insulin receptor. AZ12253801 inhibits IGF-1R–driven proliferation in 3T3 mouse fibroblasts (transfected with human IGF-1R) with an IC50 of 17 nmol/L. The IC50 for epidermal growth factor receptor (EGFR)–driven proliferation is 440 nmol/L. Anti-tumor activity. |
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