布格替尼作用机制 - Medchemexpress - MCE中国

1、Product Data SheetBrigatinibCat. No.: HY-12857CAS No.: 1197953-54-0分式: CHClNOP分量: 584.09作靶点: ALK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 Ethanol : 10 mg/mL (17.12 mM; Need ultrasonic and warming)DMSO : 2 mg/mL (3.42 mM; Need ultr

2、asonic)SolventMass1 mg 5 mg 10 mgConcentration制备储备液1 mM 1.7121 mL 8.5603 mL 17.1206 mL5 mM 0.3424 mL 1.7121 mL 3.4241 mL10 mM 0.1712 mL 0.8560 mL 1.7121 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

3、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 (0.86 mM); Clear solution此案可获得 0.5 mg/mL (0.86 mM，饱和度未知) 的澄清

4、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 (0.86 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 0.5 mg/mL (0.86 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 5.0 mg/

5、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 (0.86 mM); Clear solution此案可获得 0.5 mg/mL (0.86 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。4. 请依序添加每种溶剂： 10% EtOH 40% PEG300 5% Tween-80 45% saline

6、Solubility: 1 mg/mL (1.71 mM); Clear solution此案可获得 1 mg/mL (1.71 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 10.0 mg/mL 的澄 EtOH 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。5. 请依序添加每种溶剂： 10% EtOH 90% (20% SBE-CD in saline)Solubility: 1 mg/mL (1.71 mM); Clear solution此案可获得 1 mg/m

7、L (1.71 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 10.0 mg/mL 的澄 EtOH 储备液加到 900 L 20% 的 SBE-CD 理盐溶液中，混合均匀。6. 请依序添加每种溶剂： 10% EtOH 90% corn oilSolubility: 1 mg/mL (1.71 mM); Clear solution此案可获得 1 mg/mL (1.71 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 10.0 mg/mL 的澄 EtOH 储备液加到 900 L 油中，混合均匀。BIOLOGI

8、CAL ACTIVITY物活性 Brigatinib是有效，选择性的 ALK 抑制剂，IC50 值为 0.6 nM。IC & Target IC50: 0.6 nM (ALK)1体外研究 Brigatinib potently inhibits the in vitro kinase activity of ALK (IC50, 0.6 nM) and all five mutant variants tested,including G1202R (IC50, 0.6-6.6 nM). Brigatinib demonstrates a high degree of selectivity,

9、 only inhibiting 11 additionalnative or mutant kinases with IC50 1000 nM). In cellularassays, brigatinib inhibits ALK and ROS1 with IC50s of 14 and 18 nM, respectively. Brigatinib inhibits FLT3 and IGF-1Rwith about 11-fold lower potency (IC50, 148-158 nM) and inhibits mutant variants of FLT3 and EGF

10、R with 15- to 35-fold lower potency (IC50, 211-489 nM). Brigatinib inhibits cell growth with GI50 values ranging from 503 to 2,387 nMin three ALK-negative ALCL and NSCLC cell lines1. Brigatinib inhibits ALK activity and abrogates proliferation of ALKaddicted neuroblastoma cell lines, with IC50 of 75

11、.27 8.89 nM. Brigatinib inhibits both the ALK-I1171N and the ALK-G1269A mutant receptors at 10 and 4 nM levels, respectively3.体内研究 Brigatinib (10, 25, or 50 mg/kg once daily, p.o.) leads to a dose-dependent inhibition of tumor growth in ALK+Karpas-299 (ALCL) and H2228 (NSCLC) xenograft mouse models.

12、 Brigatinib markedly enhances survival of micebearing ALK+ brain tumors compared with PF-023410661. Brigatinib (10, 25, 50 mg/kg, p.o.) results in dose-dependent antitumor activity, with tumor regressions in a mouse model of NSCLC2.Page 2 of 3 www.MedChemEPROTOCOLKinase Assay 1 In vitro HotSpotSM ki

13、nase profiling of 289 kinases is performed. The assay is conducted in the presence of 10 M 33P-ATP, using brigatinib concentrations ranging from 0.05 nM to 1 M.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 3 Cells are seeded at 15,000 per w

14、ell with serial dilutions of the indicated inhibitors. After 72 hours cell viability isassessed by resazurin. IC50 values are calculated with GraphPad Prism 6.0 by fitting data to a log (inhibitorconcentration) vs. normalized response (variable slope) equation. Each experiment is performed in duplic

15、ate andrepeated at least three times.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice: (1) Eight- to 10-week-old female SCID/beige mice are injected intravenously with 5106 H3122 cells per mouseAdministration 2 and are randomly selected into

16、treatment groups (n=10) when the average tumor size reaches appr 300 mm3 (dayzero). Treatments are administered orally for up to 21 consecutive days at a 10 mL/kg dose volume. Subcutaneoustumors are measured two or three times weekly. Tumor volume (in mm3) is calculated using the formula (LW2)/2.Whe

17、n a tumor reaches 10% of the body weight of the host, the animal is euthanized via CO2 asphyxiation. (2) Eight-to 10-week old female SCID/beige mice are injected subcutaneously with 2.5106 Karpas-299 cells per mouse andare randomly selected into treatment groups (n=10) when the average tumor size re

18、ached appr 180 mm3 (day zero).Treatments are administered orally for 14 consecutive days at a 10 mL/kg dose volume. Tumor volume is measuredand calculated as described for the H3122 model.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Cance

19、r Discov. 2018 Jun;8(6):714-729. Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Theranostics. 2019 Jul 9;9(17):4878-4892. Pharmacol Res. 2018 Nov;137:47-55. RSC Adv. 2018 8:1182-1190.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Zhang S, et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors inPreclinical Models. Clin Cancer Res