色瑞替尼作用机制 - Medchemexpress - MCE中国

1、Product Data SheetCeritinibCat. No.: HY-15656CAS No.: 1032900-25-6分式: CHClNOS分量: 558.14作靶点: ALK; Insulin Receptor; IGF-1R作通路: Protein Tyrosine Kinase/RTK储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month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

2、.97 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 mg 10 mgConcentration制备储备液1 mM 1.7917 mL 8.9583 mL 17.9167 mL5 mM 0.3583 mL 1.7917 mL 3.5833 mL10 mM 0.1792 mL 0.8958 mL 1.7917 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：-80C, 6 months; -20C, 1 month。-80C 储存时，请

3、在 6 个内使，-20C 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 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 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 sol

4、ution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 L 5.0 mg/mL 的澄 DMSO 储备液加到 400 L PEG300 中，混合均匀；向上述体系中加50 L Tween-80，混合均匀；然后继续加 450 L 理盐定容 1 mL。2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 0.5 mg/mL (0.90 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 0.5 mg/mL (0.90 mM，

5、饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 5.0 mg/mL 的澄 DMSO 储备液加到 900 L 20% 的 SBE-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 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 L 5.0 mg/mL 的澄 DMSO 储备液加到 900 L 油中，混合均匀。BIOLOGICAL ACTIV

6、ITY物活性 Ceritinib (LDK378)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 IC50: 0.2 nM (ALK), 7 nM (InsR), 8 nM (IGF-1R), 23 nM (STK22D), 60 nM (FLT3), 260 nM (FGFR2)1体外研究 Ceritinib (LDK378) als

7、o 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) retainshigh potency against the ALK enzymatic activity with an IC50 value of 200 pM and shows only strong i

8、nhibitionagainst IGF-1R, InsR, and STK22D out of a panel of 46 kinases with a minimum selectivity of 70-fold. In Ba/F3 cellstransfected with various kinases, Ceritinib inhibits ALK activity with an IC50 value of 40.7 nM and had IC50 values of100 nM against all other kinases tested. Ceritinib (LDK378

9、) shows potent antiproliferative activity with an IC50 valueof 22.8 nM in Karpas 299 human non-Hodgkins Ki-positive large cell lymphoma carrying the NPM-ALK fusion geneand 26 nM in Ba/F3 cells transfected with the NPM-ALK fusion gene. Ceritinib also shows good selectivity over wild-type Ba/F3 cells

10、(IC502 M) 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 of50%. Ceritinib demonstrates dose-dependent tumor growth inhibition and achieved partial tumor regression

11、 in the Karpas 299 rat xenograft model with daily administration but is capable of achieving complete tumor regression inthe H2228 NSCLC rat xenograft model, which carries the EML4-ALK fusion gene. In both models, Ceritinib (LDK378) iswell tolerated in animals. Ceritinib (LDK378) is further assessed

12、 for its ADME profile and is found to have a relativelygood metabolic stability in liver microsomes, modest CYP3A4 inhibition, some hERG inhibition with an IC50 value of46 M in hERG patch clamp experiments, but no evidence of QTc prolongation in both dog and monkey telemetrystudies2.PROTOCOLAnimal I

13、n vivo PK studies are conducted in mice, rats, dogs, and cynomolgus monkeys. Ceritinib (LDK378) (HCl salt) isAdministration 1 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

14、salt) is dosed to Sprague-Dawley rats intravenously viathe tail vein at 3 mg/kg (n=3) and orally via gavage at 10 mg/kg (n=3). Blood samples are collected serially atscheduled times over 24 h after dosing. Male beagle dogs receive a single intravenous (n=2) or oral (n=3) dose ofCeritinib (phosphate

15、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 anintravenous solution at 5 mg/kg and an oral suspension at 60 mg/kg, respectively. Blood samples for

16、plasma arecollected at prescheduled times over 144 h after dosing1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Page 2 of 3 www.MedChemE户使本产品发表的科研献 Science. 2017 Dec 1;358(6367). pii: eaan4368. Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Cell

17、 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 HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Marsilje TH, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel poten

18、t 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 inphase 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