Alectinib-Hydrochloride-CH5424802-Hydrochloride-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAlectinib HydrochlorideCat. No.: HY-13011ACAS No.: 1256589-74-8Synonyms: CH5424802 (Hydrochloride); RO5424802 (Hydrochloride); AF-802 (Hydrochloride)分式: CHClNO分量: 519.08作靶點(diǎn): ALK作通路: Protein Tyrosine Kinase/RTK儲存式: Powder -20C 3

2、years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 6 mg/mL (11.56 mM; Need ultrasonic and warming)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 1.9265 mL 9.6324 mL 19.2649 mL5 mM 0.3853 mL 1.9265 mL 3.8530 mL10 mM 0.1926 mL 0.9632 mL 1.9265 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，并請注意儲備

3、液的保存式和期限。BIOLOGICAL ACTIVITY物活性 Alectinib Hydrochloride (CH5424802 Hydrochloride; RO5424802 Hydrochloride; AF-802 Hydrochloride) 是種有效、選擇性、可服的 ALK 抑制劑，IC50 值為 1.9 nM，KD) 值為 2.4 nM。IC50 & Target IC50: 1.9 nM (ALK), 1 nM (ALKF1174L), 3.5 nM (ALKR1275Q) 1Kd: 2.4 nM (ALK) 11/3 Master of Small Molecules 您

4、邊的抑制劑師www.MedChemE體外研究 Alectinib (CH5424802) prevents autophosphorylation 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

5、 anti-proliferative activity againstKARPAS-299 with an IC50 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 r

6、egression (168% tumor growth inhibition; p3 after 11 days 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 witho

7、utbody weight loss in an established ALK fusion gene-positive NSCLC xenograft model in mice 2. Alectinib at60 mg/kg causes tumor regression against EML4-ALK-positive NCI-H2228 xenograft model and decreasesthe levels of phosphorylated ALK in this model. In addition, in mice at dose levels up to 60 mg

8、/kg of Alectinib,there is no body weight loss, no significant change in peripheral blood cell count, no elevations of aspartateaminotransferase or alanine aminotransferase, and no substantial change in electrolytes. Oral administrationof Alectinib at 60 mg/kg for 4 days results in significant tumor

9、regression seen in the luminescence signal 3.PROTOCOLKinase 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 tr

10、ansfer (TR-FRET) assay or fluorescence polarization (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 byexam

11、ining the ability of the kinases to phosphorylate 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

12、theindicated time. For spheroid cell growth inhibition 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

13、 Caspase-Glo 3/7Assay 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 a

14、re 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 th

15、e 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 32/3 Master of Small Molecules 您邊的抑制劑師www.M

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

17、ctivity concentrationsin brain are 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

18、. Cancer Discov. 2016 Oct;6(10):1118-1133. 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(CH5424802). Bioorg Med Chem. 2012, 20(3), 1271-1280.3. Kodama T, et al. Antitumor activity of the selective ALK inhibitor alectinib i