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Nilotinib (AMN107) is a tyrosine kinase inhibitor of Bcr-Abl, rationally designed to bind and inhibit the c-Abl kinase active site with more affinity than the prototypic Bcr-Abl kinase inhibitor Imatinib. Nilotinib inhibits the kinases Bcr-Abl, KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK. Nilotinib possesses an in vitro Bcr-Abl binding potency 30 times greater than imatinib in imatinib-resistant cells, and 5-7 times greater than imatinib in imatinib-susceptible leukemic cells. Nilotinib also induces cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Nilotinib (AMN107) is more potent than imatinib against CML cells by a factor of 20 to 50.
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Source | J Clin Pharmacol (2015). Figure 3. Nilotinib |
| Method | ||
| Cell Lines | blood samples | |
| Concentrations | 2.5 ng/mL | |
| Incubation Time | 24, 48, and 72 h | |
| Results | Following a single-dose of midazolam of 2 mg on Day 1, midazolam was rapidly absorbed and eliminated with a Cmax of 12.4 ng/mL and AUCinf of 37.0 ng.h/mL. Coadministration with repeated-doses of nilotinib increased the Cmax to 24.1 ng/mL and AUCinf to 88.8 ng.h/mL. |
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Source | J Clin Pharmacol (2015). Figure 2. Nilotinib |
| Method | DDI study | |
| Cell Lines | ||
| Concentrations | 2 mg/mL | |
| Incubation Time | 7-day | |
| Results | The mean plasma concentration-time profiles of midazolam dosing alone and in combination with nilotinib are displayed in Figure 2a. |
| Cell Experiment | |
|---|---|
| Cell lines | V560G-KIT and D816-KIT cell |
| Preparation method | Cell proliferation studies Cells were incubated for 24 hours in complete medium containing up to 10 μmol/L of drug. Viable cells, based on cell size, were then counted using a CDA-500 cell counter (Sysmex Corp.). Duplicate samples at each drug concentration were averaged and cell proliferation then expressed as a percentage of cells in the vehicle control samples. |
| Concentrations | 0~10 μ M |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | DBA2/J mice bearing a V560G-KIT and D816V-KIT tumor model |
| Formulation | 10% N-methylpyrrolidinone, 90% polyethylene glycol 300 |
| Dosages | 100 mg/kg once daily |
| Administration | orally |
| Molecular Weight | 529.52 |
| Formula | C28H22F3N7O |
| CAS Number | 641571-10-0 |
| Solubility (25°C) | DMSO 16 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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Risvodetinib (IkT-148009) is an orally active, selective and brain-penetrant protein tyrosine kinase inhibitor, displaying excellent target efficacy against c-Abl1, c-Abl2/Arg with IC50 values of 33 nM, 14 nM, respectively. |
| SI-2 hydrochloride
SI-2 hydrochloride is a highly promising SRC-3 inhibitor (PPI) with acceptable oral availability, with IC50 values of 3-20 nM for breast cancer cell death. |
| KB SRC 4
KB SRC 4 is a potent, and highly selective c-Src inhibitor, with a Ki of 44 nM and a Kd of 86 nM, and shows no inhibition on c-Abl up to 125 μM; KB SRC 4 has antitumor activity. |
| Hydroxymethyl dasatinib
Hydroxymethyl dasatinib (M24), a benzylhydroxy metabolite of Dasatinib, exhibits an IC50 of 46.7nM in K562 CML cells. |
| Asciminib hydrochloride
Asciminib (ABL001) hydrochloride is a potent and selective allosteric BCR-ABL1 inhibitor, which inhibits Ba/F3 cells grown with an IC50 of 0.25 nM. |
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