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Ceritinib dihydrochloride

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Chemical Structure| 1380575-43-8 同义名 : LDK378 dihydrochloride;Zykadia
CAS号 : 1380575-43-8
货号 : A372261
分子式 : C28H38Cl3N5O3S
纯度 : 98%
分子量 : 631.057
MDL号 : MFCD26142928
存储条件：

粉末 Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(166.39 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO

H2O: 10 mg/mL(15.85 mM)，配合低频超声助溶
动物实验配方：
生物活性
描述 Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin receptor superfamily. Altered expression and hyperactivation of ALK as a consequence of translocations or point mutations has been demonstrated to be an essential oncogenic lesion in a number of cancers. LDK378 2HCl, which is currently in Phase 1 and 2 clinical trials, is a potent ALK inhibitor with an IC50 of 0.2 nM in a cell-free assay. It also inhibits IGF-1R, InSR, STK22D and FLT3 with IC50 values of 8 nM, 7 nM, 23 nM and 60 nM, respectively. LDK378 exhibited antiproliferative activity especially on BA/F3-NPM-ALK and Karpas290 cells with IC50 values of 26.0 nM and 22.8 nM, and on BA/F3-TEL-INSR and BA/F3-WT cells with IC50 values of 319.5 nM and 2477 nM, respectively. In 2-week Karpas299 rat xenograft models, LDK378 induced a dose-dependent growth inhibition (tumor growth inhibition factor [T/C] = 74% at 6.25 mg/kg; T/C = 30% at 12.5 mg/kg) and tumor regression (T/C = -33% at 25 mg/kg and T/C = -66% at 50 mg/kg). In 2-week H2228 rat xenograft models, LDK378 induced a dose-dependent growth inhibition (T/C = 67% at 5 mg/kg; T/C = 2% at 10 mg/kg) and complete tumor regression at 25mg/kg (T/C = -100% at 25 mg/kg). Moreover, LDK378 was well tolerated and no body weight loss was observed at all doses tested in both models[2].
作用机制 The central pyrimidine ring of LDK378 is sandwiched between Ala1148 and Leu1256 and its chlorine substituent is directed towards the back of the pocket making hydrophobic contact with gatekeeper Leu1196[2].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.58mL

0.32mL

0.16mL

7.92mL

1.58mL

0.79mL

15.85mL

3.17mL

1.58mL
参考文献

[1]Marsilje TH, Pei W, 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-(isopropylsulf onyl)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]Marsilje TH, et al. J Med Chem. 2013 Jul 25;56(14):5675-90