1、Product Data SheetCeritinibCat. No.: HY-15656CAS No.: 1032900-25-6分式: CHClNOS分量: 558.14作靶點(diǎn): ALK; Insulin Receptor; IGF-1R作通路: Protein Tyrosine Kinase/RTK儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗 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制備儲備液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請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；旦配成溶液，請分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請

3、在 6 個內(nèi)使，-20C 儲存時，請在 1 個內(nèi)使。體內(nèi)實(shí)驗請根據(jù)您的實(shí)驗動物和給藥式選擇適當(dāng)?shù)娜芙獍?。以下溶解案都請先按?In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實(shí)驗結(jié)果的可靠性，澄 的儲備液可以根據(jù)儲存條件，適當(dāng)保存；體內(nèi)實(shí)驗的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 0.5 mg/mL (0.90 mM); Clear sol

4、ution此案可獲得 0.5 mg/mL (0.90 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 5.0 mg/mL 的澄 DMSO 儲備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 0.5 mg/mL (0.90 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 0.5 mg/mL (0.90 mM，

5、飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 5.0 mg/mL 的澄 DMSO 儲備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻。3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 0.5 mg/mL (0.90 mM); Clear solution此案可獲得 0.5 mg/mL (0.90 mM，飽和度未知) 的澄 溶液，此案不適于實(shí)驗周 期在半個以上的實(shí)驗。以 1 mL 作液為例，取 100 L 5.0 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIV

6、ITY物活性 Ceritinib (LDK378)種選擇性，服可物利且具有 ATP 競爭性的 ALK 酪氨酸激酶抑制劑，IC50 為 200 pM。Ceritinib (LDK378) 還抑制 IGF-1R，InsR 和 STK22D，IC50 值分別為 8、7 和 23 nM。Ceritinib (LDK378) 顯出良好抗腫瘤效。IC & Target IC50: 0.2 nM (ALK), 7 nM (InsR), 8 nM (IGF-1R), 23 nM (STK22D), 60 nM (FLT3), 260 nM (FGFR2)1體外研究 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.體內(nèi)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戶使本產(chǎn)品發(fā)表的科研獻(xiàn) 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