Ceritinib (LDK378) is a selective, orally bioavailable, and ATP-competitive ALK tyrosine kinase inhibitor with an IC₅₀ of 200 pM. Ceritinib (LDK378) also inhibits IGF-1R, InsR, and STK22D with IC₅₀ values of 8, 7, and 23 nM, respectively. Ceritinib (LDK378) shows great antitumor potency^[1][2].

IC50: 0.2 nM (ALK), 7 nM (InsR), 8 nM (IGF-1R), 23 nM (STK22D), 60 nM (FLT3), 260 nM (FGFR2)^[1]

Ceritinib (LDK378) also inhibits RET (IC₅₀=400 nM), FGFR3 (IC₅₀=430 nM), LCK (IC₅₀=560 nM), JAK2 (IC₅₀=610 nM), Aurora (IC₅₀=660 nM), LYN (₅₀=840 nM), EGFR (IC₅₀=900 nM), and FGFR4 (IC₅₀=950 nM)^[1]. Ceritinib (LDK378) retains high potency against the ALK enzymatic activity with an IC₅₀ value of 200 pM and shows only strong inhibition against IGF-1R, InsR, and STK22D out of a panel of 46 kinases with a minimum selectivity of 70-fold. In Ba/F3 cells transfected with various kinases, Ceritinib inhibits ALK activity with an IC₅₀ value of 40.7 nM and had IC₅₀ values of >100 nM against all other kinases tested. Ceritinib (LDK378) shows potent antiproliferative activity with an IC₅₀ value of 22.8 nM in Karpas 299 human non-Hodgkin’s K_i-positive large cell lymphoma carrying the NPM-ALK fusion gene and 26 nM in Ba/F3 cells transfected with the NPM-ALK fusion gene. Ceritinib also shows good selectivity over wild-type Ba/F3 cells (IC₅₀>2 μM) and Ba/F3 cells transfected with Tel-InsR gene (IC₅₀=320 nM)^[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.

Ceritinib (LDK378) has an excellent pharmacokinetics profile in rodents and non-rodents with an oral bioavailability of >50%. Ceritinib demonstrates dose-dependent tumor growth inhibition and achieved partial tumor regression in the Karpas 299 rat xenograft model with daily administration but is capable of achieving complete tumor regression in the H2228 NSCLC rat xenograft model, which carries the EML4-ALK fusion gene. In both models, Ceritinib (LDK378) is well tolerated in animals. Ceritinib (LDK378) is further assessed for its ADME profile and is found to have a relatively good metabolic stability in liver microsomes, modest CYP3A4 inhibition, some hERG inhibition with an IC₅₀ value of 46 μM in hERG patch clamp experiments, but no evidence of QTc prolongation in both dog and monkey telemetry studies^[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.

558.14

C₂₈H₃₆ClN₅O₃S

1032900-25-6

色瑞替尼

Room temperature in continental US; may vary elsewhere.

DMSO : 5.6 mg/mL (10.03 mM; Need ultrasonic)

Ethanol : ≥ 3.33 mg/mL (5.97 mM)

* “≥” means soluble, but saturation unknown.

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。

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: ≥ 0.5 mg/mL (0.90 mM); Clear solution

  此方案可获得 ≥ 0.5 mg/mL (0.90 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 5.0 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: ≥ 0.5 mg/mL (0.90 mM); Clear solution

  此方案可获得 ≥ 0.5 mg/mL (0.90 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 5.0 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: ≥ 0.5 mg/mL (0.90 mM); Clear solution

  此方案可获得 ≥ 0.5 mg/mL (0.90 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 5.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

• [1]. Marsilje TH, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90.

  [2]. Chen J, et al. LDK378: a promising anaplastic lymphoma kinase (ALK) inhibitor. J Med Chem. 2013 Jul 25;56(14):5673-4.

  [3]. Tucker ER, et al. Immunoassays for the quantification of ALK and phosphorylated ALK support the evaluation of on-target ALK inhibitors in neuroblastoma. Mol Oncol. 2017 Aug;11(8):996-1006.

  [4]. Rothschild SI. Ceritinib-a second-generation ALK inhibitor overcoming resistance in ALK-rearranged non-small celllung cancer. Transl Lung Cancer Res. 2014 Dec;3(6):379-81.

In vivo PK studies are conducted in mice, rats, dogs, and cynomolgus monkeys. Ceritinib (LDK378) (HCl salt) is administered to male Balb/c mice intravenously via tail vein at 5 mg/kg (n=3) and orally via gavage at 20 mg/kg (n=3). By use of the same formulation, Ceritinib (LDK378) (HCl salt) is dosed to Sprague-Dawley rats intravenously via the tail vein at 3 mg/kg (n=3) and orally via gavage at 10 mg/kg (n=3). Blood samples are collected serially at scheduled times over 24 h after dosing. Male beagle dogs receive a single intravenous (n=2) or oral (n=3) dose of Ceritinib (phosphate salt) as an intravenous solution at 5 mg/kg and an oral suspension at 20 mg/kg, respectively. Male cynomologus monkeys receive single intravenous (n=2) or oral (n=3) dose of Ceritinib (free base) as an intravenous solution at 5 mg/kg and an oral suspension at 60 mg/kg, respectively. Blood samples for plasma are collected at prescheduled times over 144 h after dosing^[1].

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]. Marsilje TH, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90.

  [2]. Chen J, et al. LDK378: a promising anaplastic lymphoma kinase (ALK) inhibitor. J Med Chem. 2013 Jul 25;56(14):5673-4.

  [3]. Tucker ER, et al. Immunoassays for the quantification of ALK and phosphorylated ALK support the evaluation of on-target ALK inhibitors in neuroblastoma. Mol Oncol. 2017 Aug;11(8):996-1006.

  [4]. Rothschild SI. Ceritinib-a second-generation ALK inhibitor overcoming resistance in ALK-rearranged non-small celllung cancer. Transl Lung Cancer Res. 2014 Dec;3(6):379-81.