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In vitro: Nilotinib (AMN107) is significantly more potent against BCR-ABL than imatinib, and is active against many imatinib-resistant BCR-ABL mutants. Nilotinib inhibits proliferation, migration, and actin filament formation, as well as the expression of α-SMA and collagen in activated HSCs. Nilotinib induces apoptosis of HSCs, which is correlated with reduced bcl-2 expression, increases p53 expression, cleavage of PARP, as well as increases expression of PPARγ and TRAIL-R. Nilotinib also induces cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibits activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibits PDGF and TGFβ-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFβ-activated phosphorylated form(s) of Abl in human HSCs are inhibited by Nilotinib. In vivo: exposure of a variety of BCR-ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR-ABL point mutations causing resistance to imatinib in patients. Nilotinib reduces collagen deposition and α-SMA expression in CCl4 and BDL-induced fibrosis. Nilotinib could induce HSC undergoing apoptosis, which is correlated with downregulation of bcl-2. AMN107 prolongs survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolongs survival in imatinib-resistant CML mouse models.
| Molecular Weight | 583.99 |
| Formula | C28H25ClF3N7O2 |
| CAS Number | 923288-90-8 |
| Solubility (25°C) | ≥ 33 mg/mL in DMSO |
| 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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| Osteogenic Growth Peptide (10-14)
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| Abl Cytosolic Substrate
Abl Cytosolic Substrate is a substrate for Abelson tyrosine kinase (Abl ). |
| Ac-Tyr(PO3H2)-Glu-Glu-Ile-Glu-OH
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