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Product Data?SheetCeritinibCat. No.:CAS No.:分?式:分?量:作?靶点:作?通路:储存?式:HY-156561032900-25-6C??H??ClN?O?S558.14ALK; Insulin Receptor; IGF-1RProtein Tyrosine Kinase/RTKPowderIn solvent-20°C4°C-80°C-20°C3 years2 years6 months1 monthInhibitors?Agonists?Screening Libraries溶解性数据体外实验DMSO : 5.6 mg/mL (10.03 mM; Need ultrasonic)Ethanol : ≥ 3.33 mg/mL (5.97 mM)* \Mass1 mg5 mg10 mgSolventConcentration制备储备液1 mM5 mM10 mM1.7917 mL0.3583 mL0.1792 mL8.9583 mL1.7917 mL0.8958 mL17.9167 mL3.5833 mL1.7917 mL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；?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?式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个?内使?，-20°C 储存时，请在 1 个?内使?。体内实验请根据您的实验动物和给药?式选择适当的溶解?案。以下溶解?案都请先按照 In Vitro ?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?作液，建议您现?现配，当天使?； 以下溶剂前显?的百分?是指该溶剂在您配制终溶液中的体积占?；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?式助溶1. 请依序添加每种溶剂：?10% DMSO ?? 40% PEG300 ?? 5% Tween-80 ?? 45% salineSolubility: ≥ 0.5 mg/mL (0.90 mM); Clear solution此?案可获得 ≥ 0.5 mg/mL (0.90 mM，饱和度未知) 的澄清溶液。 以 1 mL ?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? 50 μL Tween-80，混合均匀；然后继续加? 450 μL ?理盐?定容? 1 mL。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 solutionPage 1 of 2 www.MedChemExpress.cn

此?案可获得 ≥ 0.5 mg/mL (0.90 mM，饱和度未知) 的澄清溶液。 以 1 mL ?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 ?理盐??溶液中，混合均匀。3. 请依序添加每种溶剂：?10% DMSO ?? 90% corn oilSolubility: ≥ 0.5 mg/mL (0.90 mM); Clear solution此?案可获得 ≥ 0.5 mg/mL (0.90 mM，饱和度未知) 的澄清溶液，此?案不适?于实验周期在半个?以上的实验。 以 1 mL ?作液为例，取 100 μL 5.0 mg/mL 的澄清 DMSO 储备液加到 900 μL ??油中，混合均匀。BIOLOGICAL ACTIVITY?物活性Ceritinib (LDK378) 是?种选择性，?服可?物利?且具有 ATP 竞争性的 ALK 酪氨酸激酶抑制剂，IC50 为 200 pM。 Ceritinib (LDK378) 还抑制 IGF-1R，InsR 和 STK22D，IC50 值分别为 8、7 和 23 nM。Ceritinib (LDK378) 显?出良好抗肿瘤效?。IC?? & Target体外研究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 Ki-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].体内研究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].PROTOCOLAnimal Administration [1]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].MCE has not independently confirmed the accuracy of these methods. They are for reference only.Page 2 of 3

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????Science. 2017 Dec 1;358(6367). pii: eaan4368.????Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093.????Cell Chem Biol. 2018 Aug 16;25(8):996-1005.e4.????Sci Signal. 2015 Dec 8;8(406):ra125.????Mol Oncol. 2017 Aug;11(8):996-1006.

See more customer validations on www.MedChemExpress.cnREFERENCES

[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.

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