Nilotinib is an orally available Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity.

Bcr-Abl^[1]

The novel, selective Abl inhibitor, Nilotinib (AMN107), is designed to interact with the ATP-binding site of BCR-ABL with a higher affinity than Imatinib. In addition to being significantly more potent compared with Imatinib (IC₅₀<30 nm), nilotinib also maintains activity against most of the bcr-abl point mutants that confer imatinib resistance^[1]. Nilotinib demonstrates significant antitumor efficacy against GIST xenograft lines and Imatinib-resistant GIST cell lines. The parent cell lines GK1C and GK3C show Imatinib sensitivity with IC₅₀ of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The Imatinib-resistant cell lines GK1C-IR and GK3C-IR show Imatinib resistance with IC₅₀ values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

The percentage of tumor growth inhibition (TGI) is 83.8% for Imatinib and 69.6% for Nilotinib in the GK1X xenograft line (n.s.). In the GK2X xenograft line, TGI is 83.0% for Imatinib and 85.3% for Nilotinib (n.s.). Additionally, the GK3X xenograft line TGI is 31.1% for Imatinib and 47.5% for Nilotinib (n.s.). These results suggest that, except for the GK1X xenograft line, Nilotinib shows equivalent or higher antitumor effects than Imatinib^[2]. Nilotinib has a significant healing effect on the macroscopic and microscopic pathologic scores and ensures considerable mucosal healing in the indomethacin-induced enterocolitis rat model. While Nilotinib decreased the PDGFR α and β levels and apoptotic scores in the colon, it did not have a significant effect on the weight and TNF-α levels. Further experimental investigations could provide more definitive evidence for humans^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

529.52

C₂₈H₂₂F₃N₇O

641571-10-0

尼洛替尼；尼罗替尼

Room temperature in continental US; may vary elsewhere.

DMSO : < 1 mg/mL (ultrasonic;warming;heat to 60°C) (insoluble or slightly soluble)

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

  Solubility: ≥ 0.6 mg/mL (1.13 mM); Clear solution

  此方案可获得 ≥ 0.6 mg/mL (1.13 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 6.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH₂O 中，得到澄清透明的生理盐水溶液

• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

  Solubility: ≥ 0.6 mg/mL (1.13 mM); Suspended solution

  此方案可获得 ≥ 0.6 mg/mL (1.13 mM，饱和度未知) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。

  以 1 mL 工作液为例，取 100 μL 6.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 3.

  请依序添加每种溶剂： 10% DMSO    90% corn oil

  Solubility: ≥ 0.6 mg/mL (1.13 mM); Clear solution

  此方案可获得 ≥ 0.6 mg/mL (1.13 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。

  以 1 mL 工作液为例，取 100 μL 6.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [1]. Weisberg E, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood. 2007 Mar 1;109(5):2112-20.

  [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]. Dervis Hakim G, et al. Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model. World J Gastroenterol. 2015 Nov 28;21(44):12576-85.

  [4]. 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.

  [5]. Meirson T, et al. Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors. Oncotarget. 2018 Apr 24;9(31):22158-22183.

The human GIST cell lines GK1C and GK3C, and the Imatinib-resistant cell lines GK1C-IR and GK3C-IR are plated in 96-well microplates and cultured for 12 h before exposure to Imatinib (1-100 µM) or Nilotinib (1-100 µM) for 72 h. The cells are quantified by the WST-8 assay. The optical density (OD) is determined with Sunrise rainbow. The rate of inhibition is calculated as follows: % of inhibition=(OD of treated group-blank)/(OD of control group-blank)×100%. The concentration of tested drugs resulting in 50% growth inhibition (IC₅₀) is calculated^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Mice^[2]
The GIST xenograft lines GK1X, GK2X and GK3X in nude mice are used. These xenograft lines are maintained by continual passage in BALB/cSLc-nu/nu mice. Mice bearing GK1X, GK2X and GK3X tumors (6-8 mice per group) are treated daily with vehicle or 40 mg/kg Imatinib or Nilotinib for 4 weeks. Tumor volume (TV) is determined from caliper measurements of tumor length (L) and width (w) according to the formula LW²/2. TV is determined every two to three days and on the day of evaluation. Mice are sacrificed and the percentage of tumor growth inhibition (TGI) is 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.
Rats^[3]
Female Wistar albino rats, weighing 226-243 g (mean weight, 241.09 g), for use in this study. Nilotinib, administered 20 mg/kg/d in two divided doses, is administered to the Nilotinib group of rats (n=7) for 13 d through an orogastric tube, beginning on the same day as indomethacin administration. Blood and tissue samples for pathological examination are obtained from all rats under ether anesthesia at the end of the 13-d period. All animals are then sacrificed by decapitation.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Weisberg E, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood. 2007 Mar 1;109(5):2112-20.

  [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]. Dervis Hakim G, et al. Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model. World J Gastroenterol. 2015 Nov 28;21(44):12576-85.

  [4]. 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.

  [5]. Meirson T, et al. Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors. Oncotarget. 2018 Apr 24;9(31):22158-22183.