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Nilotinib
Catalog No. T1524 CAS 641571-10-0
Synonyms: Tasigna, AMN107
Nilotinib (AMN107) is a second-generation Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity.
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Nilotinib, CAS 641571-10-0
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50 mg
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1 mL * 10 mM (in DMSO)
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Purity: 99.83%
Purity: 99.61%
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Biological Description
Chemical Properties
Storage & Solubility Information
Description
Nilotinib (AMN107) is a second-generation Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity.
Targets&IC50
Abl (WT):15 nM (cell free)
In vitro
Nilotinib (AMN107) inhibited Abl-catalyzed peptide substrate phosphorylation with ~20-fold higher potency than imatinib (IC50: 15 versus 280 nmol/L). AMN107 inhibited the growth of cells expressing wild-type Bcr-Abl with 20-fold higher potency than imatinib (IC50: 13 versus 260 nmol/L) [1].Parent and imatinib-resistant GIST cell lines showed sensitivity to nilotinib in a concentration-dependent manner with the IC50 values of parent GIST cell lines being 3.15±0.31 μM for GK1C and 3.32±0.18 μM for GK3C (n.s.), and the imatinib-resistant cell lines showing IC50 values of 4.10±0.46 μM and 3.96±0.19 μM for GK1C-IR and GK3C-IR (n.s.), respectively [2]. Nilotinib inhibited proliferation, migration, and actin filament formation, as well as the expression of α-SMA and collagen in activated HSCs. Nilotinib induced apoptosis of HSCs. Nilotinib also induced cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1 [3].
In vivo
The percentage of tumor growth inhibition (TGI) was 69.6% for nilotinib in the GK1X xenograft line. In the GK2X xenograft line, TGI was 85.3% for nilotinib [2]. Imatinib and nilotinib attenuated the extent of lung injury and fibrosis. The numbers of inflammatory cells and levels of IL-6, IL-1β and tumor necrosis factor-α were decreased in the imatinib and nilotinib groups on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline on days 14 and 21, which was accompanied by decreased expression levels of TGF-β1 and PDGFR-β [4].
Kinase Assay
Kinase assays using wild-type and mutant glutathione S-transferase (GST)–Abl fusion proteins (c-Abl amino acids 220-498) were done as described, with minor alterations. GST-Abl fusion proteins were released from glutathione-Sepharose beads before use; the concentration of ATP was 5 μmol/L. Immediately before use in kinase autophosphorylation and in vitro peptide substrate phosphorylation assays, GST-Abl kinase domain fusion proteins were treated with LAR tyrosine phosphatase according to the manufacturer's instructions. After 1-hour incubation at 30°C, LAR phosphatase was inactivated by addition of sodium vanadate (1 mmol/L). Immunoblot analysis comparing untreated GST-Abl kinase to dephosphorylated GST-Abl kinase was routinely done using phosphotyrosine-specific antibody 4G10 to confirm complete (>95%) dephosphorylation of tyrosine residues and c-Abl antibody CST 2862 to confirm equal loading of GST-Abl kinase. The inhibitor concentration ranges for IC50 determinations were 0 to 5,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The BMS-354825 concentration range was extended to 1,000 nmol/L for mutant T315I. These same inhibitor concentrations were used for the in vitro peptide substrate phosphorylation assays. The three inhibitors were tested over these same concentration ranges against GST-Src kinase and GST-Lyn kinase [1].
Cell Research
Ba/F3 cell lines were plated in triplicate and incubated with escalating concentrations of imatinib, AMN107, or BMS-354825 for 72 hours. Proliferation was measured using a methanethiosulfonate-based viability assay. IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges for IC50 and IC90 determinations were 0 to 2,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The imatinib concentration range was extended to 6,400 nmol/L for mutants with IC50 >2,000 nmol/L. The BMS-354825 concentration range was extended to 200 nmol/L for mutant T315I [1].
Animal Research
The GIST xenograft lines GK1X, GK2X and GK3X in nude mice were established from GIST patients as described in our previous study [10]. These xenograft lines were maintained by continual passage in BALB/cSLc-nu/nu mice. Mice bearing GK1X, GK2X and GK3X tumors (6–8 mice per group) were treated daily with vehicle or 40 mg/kg imatinib or nilotinib for 4 weeks. Tumor volume (TV) was determined from caliper measurements of tumor length (L) and width (w) according to the formula LW2/2. TV was determined every two to three days and on the day of evaluation. Mice were sacrificed and the percentage of tumor growth inhibition (TGI) was calculated as follows: TGI (%) ?=? [1– (mean of treatment group tumor volume on evaluation day – mean of treatment group tumor volume on day 1)/(mean of control group tumor volume on evaluation day – mean of control group tumor volume on day 1)]×100 [2].
Synonyms
Tasigna, AMN107
Molecular Weight
529.52
Formula
C28H22F3N7O
CAS No.
641571-10-0
Storage
Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Solubility Information
H2O: < 1 mg/mL (insoluble or slightly soluble)
Ethanol: < 1 mg/mL (insoluble or slightly soluble)
DMSO: 13.75 mg/mL (25.97 mM)
References and Literature
1. O'Hare T, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005 Jun 1;65(11):4500-5. 2. Sako H, et al. Antitumor effect of the tyrosine kinase inhibitor Nilotinib on gastrointestinal stromal tumor (GIST) and Imatinib-resistant GIST cells. PLoS One. 2014 Sep 15;9(9):e107613. 3. Liu Y, et al. Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib. J Hepatol. 2011 Sep;55(3):612-625. 4. Rhee CK, et al. Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Respiration. 2011;82(3):273-87. 6. Fujita KI, et al. Involvement of the Transporters P-Glycoprotein and Breast Cancer Resistance Protein in Dermal Distribution of the Multikinase Inhibitor Regorafenib and Its Active Metabolites. J Pharm Sci. 2017 Sep;106(9):2632-2641. 7. Sun R, Bao M Y, Long X, et al. Metabolic gene NR4A1 as a potential therapeutic target for non‐smoking female non‐small cell lung cancer patients[J]. Thoracic cancer. 2019 Apr;10(4):715-727. 8. Kuang Y, Chai Y, Xu L, et al. Glabrone as a specific UGT1A9 probe substrate and its application in discovering the inhibitor glycycoumarin[J]. European Journal of Pharmaceutical Sciences. 2021: 105786.
Citations
1. Cheng S, Jin P, Li H, et al. Evaluation of CML TKI Induced Cardiovascular Toxicity and Development of Potential Rescue Strategies in a Zebrafish Model. Frontiers in Pharmacology. 2021: 2866. 2. Kuang Y, Chai Y, Xu L, et al. Glabrone as a specific UGT1A9 probe substrate and its application in discovering the inhibitor glycycoumarin. European Journal of Pharmaceutical Sciences. 2021: 105786. 3. Sun R, Bao M Y, Long X, et al. Metabolic gene NR4A1 as a potential therapeutic target for non‐smoking female non‐small cell lung cancer patients. Thoracic Cancer. 2019 Apr;10(4):715-727 4. Yan H, Wu W, Hu Y, et al.Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis.Nature Communications.2023, 14(1): 2756. 5. Liu T, Yue X, Chen X, et al.Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma.Cellular Oncology.2024: 1-18.
Related compound libraries
This product is contained In the following compound libraries:
Anti-Cancer Clinical Compound Library EMA Approved Drug Library Drug Repurposing Compound Library Tyrosine Kinase Inhibitor Library Kinase Inhibitor Library FDA-Approved Kinase Inhibitor Library Anti-Cancer Approved Drug Library Anti-Cancer Drug Library Inhibitor Library Anti-Cancer Active Compound Library
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO (Master liquid concentration mg/mL),
Method for preparing in vivo formulation:Take μL DMSO master liquid, next add μL PEG300, mix and clarify, next add μL Tween 80,mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation:Take μL DMSO master liquid, next add μL Corn oil,mix and clarify.
Note:
Be sure to add the solvent(s) in order. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
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