Alectinib-CH5424802-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAlectinibCat. No.: HY-13011CAS No.: 1256580-46-7Synonyms: CH5424802; RO5424802; AF802分式: CHNO分量: 482.62作靶點(diǎn): ALK作通路: Protein Tyrosine Kinase/RTK儲(chǔ)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(yàn) DMSO

2、: 6.2 mg/mL (12.85 mM; Need warming)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 0.38 mg/mL (0.79 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 0.38 mg/mL (0.79 mM); Precipitated solution; Need ultrasonic1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE3. 請(qǐng)依序添

3、加每種溶劑： 10% DMSO 90% corn oilSolubility: 0.38 mg/mL (0.79 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Alectinib (CH5424802; RO5424802; AF802)種有效，選擇性和可服的 ALK 抑制劑，IC50 為1.9 nM。IC50 & Target IC50: 1.9 nM(ALK), 1 nM (ALKF1174L), 3.5 nM (ALKR1275Q) 1Kd: 2.4 nM (ALK) 1體外研究 Alectinib (CH5424802) prevents auto

4、phosphorylation of ALK in NCI-H2228 NSCLC cells expressing EML4-ALK, and Alectinib also results in substantial suppression of phosphorylation of STAT3 and AKT, but not ofERK1/2 1. Alectinib (CH5424802) shows high kinase selectivity and strong anti-proliferative activity againstKARPAS-299 with an IC5

5、0 value of 3 nM 2.體內(nèi)研究 In the NCI-H2228 model, once-daily oral administration of Alectinib (CH5424802) results in dose-dependenttumor growth inhibition (ED50=0.46 mg/kg) and tumor regression. Treatment of 20 mg/kg Alectinib showsrapid tumor regression (168% tumor growth inhibition; p3 after 11 days

6、of treatment (at day 28), a potentantitumor effect is maintained, and tumor re-growth dpes not occur throughout the 4-week drug-free period1. Oral administration of Alectinib (CH5424802) at 20 mg/kg displays significant tumor regression withoutbody weight loss in an established ALK fusion gene-posit

7、ive NSCLC xenograft model in mice 2. Alectinib(Alectinib) at 60 mg/kg causes tumor regression against EML4-ALK-positive NCI-H2228 xenograft model anddecreases the levels of phosphorylated ALK in this model. In addition, in mice at dose levels up to 60 mg/kgof CH5424802, there is no body weight loss,

8、 no significant change in peripheral blood cell count, noelevations of aspartate aminotransferase or alanine aminotransferase, and no substantial change inelectrolytes. Oral administration of CH5424802 at 60 mg/kg for 4 days results in significant tumor regressionseen in the luminescence signal 3.PR

9、OTOCOLKinase Assay 1 The inhibitory ability against each kinase except for MEK1 and Raf-1 is evaluated by examining their ability tophosphorylate various substrate peptides in the presence of Alectinib using time-resolved fluorescenceresonance energy transfer (TR-FRET) assay or fluorescence polariza

10、tion (FP) assay. The inhibitory activityagainst MEK1 is evaluated by quantitative analysis of the phosphorylation of a substrate peptide by arecombinant ERK2 protein in the presence of Alectinib. The inhibitory activity against Raf-1 is evaluated byexamining the ability of the kinases to phosphoryla

11、te MEK1 in the presence of Alectinib 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 Cells are cultured in 96-well plates overnight and incubated with various concentrations of Alectinib for theindicated time. For spheroid cell growth inh

12、ibition assay, cells are seeded on spheroid plates, incubatedovernight, and then treated with Alectinib for the indicated times. The viable cells are measured by theCellTiter-Glo Luminescent Cell Viability Assay. Caspase-3/7 assay is evaluated using the Caspase-Glo 3/72/3 Master of Small Molecules 您

13、邊的抑制劑師www.MedChemEAssay Kit 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 13 Cell lines are grown as s.c. tumors in SCID or nude mice. Therapeutic experiments are started (day 0) whenthe tumor reaches 250 or 350 mm3. Mice

14、 are randomized to treatment groups to receive vehicle orAlectinib (oral, qd) for the indicated duration. Final concentration of vehicle is 0.02 N HCl, 10% DMSO, 10%Cremophor EL, 15% PEG400, and 15% HPCD (2-hydroxypropyl-cyclodextrin). The length (L) and width(W) of the tumor mass are measured, and

15、the tumor volume (TV) is calculated as: TV=(LW2)/2. Tumorgrowth inhibition is calculated using the following formula: tumor growth inhibition=1(TT0)/(CC0)100.The ED50 is calculated from the values of tumor growth inhibition on the final experimental day.Rats 3Plasma and brain (cerebrum and cerebellu

16、m) samples are prepared at various time points between 4 and168 h after a single oral administration of 14C-labeled Alectinib (Alectinib) at 1 mg/kg to a rat. Theradioactivity concentrations in plasma are determined by a liquid scintillation counter, and the radioactivityconcentrations in brain are

17、quantified using quantitative whole-body autography.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Science. 2017 Dec 1;358(6367). Science. 2014 Oct 3;346(6205):1255784. Cancer Discov. 2018 Jun;8(6):714-729. Cancer Discov. 2016 Oct;6(10):111

18、8-1133. Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Sakamoto H, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011, 19(5),679-690.2. Kinoshita K, et al. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor(C