Avagacestat-BMS-708163-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAvagacestatCat. No.: HY-50845CAS No.: 1146699-66-2Synonyms: BMS-708163分式: CHClFNOS分量: 520.89作靶點: -secretase; Notch作通路: Neuronal Signaling; Stem Cell/Wnt儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體

2、外實驗 DMSO : 100 mg/mL (191.98 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 3 mg/mL (5.76 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% corn oil1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 3 mg/mL (5.76 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Avagacestat (BMS-708163)有效的 -sec

3、retase 抑制劑，抑制 A42 和 A40 的產(chǎn)，IC50 值分別為 0.27nM 和 0.30 nM；BMS-708163 同時抑制 Notch 胞內(nèi)結(jié)構(gòu)域 (NICD) 和 CYP2C19，IC50 值分別為 0.84 nM 和 20M。IC50 & Target IC50: 0.27 nM (-secretase, A42), 0.30 nM (-secretase, A40), 20 M (CYP2C19) 1, 0.84 nM (NICD) 2體外研究 Avagacestat (BMS-708163) exhibits weaker potency for inhibition

4、of Notch processing, IC50=5823 nM, ascompared to its inhibition potency for APP cleavage 1. Avagacestat (BMS-708163) (10M) combined withgefitinib significantly attenuates the colony growth of PC9/AB2 cells, increases the expression of activecaspase 3 and PARP and reduces the expression of Ki-67 in P

5、C9/AB2 cells. Avagacestat (BMS-708163)induces apoptosis and enhances cell cycle arrest at the G1 phase in PC9/AB2 cells. Avagacestat (BMS-708163) treatment effectively downregulates the expression of Notch1, HES1, PI3K and Akt in PC9/AB2 cells3.體內(nèi)研究 Avagacestat (BMS-708163) significantly reduces bot

6、h plasma and brain A40 levels relative to control at 10and 100 mg/kg for the entire dosing interval, demonstrates significant A40 lowering for 8 h after an oraldose of 1 mg/kg, and significantly lowers CSF A40 levels in rats, when measured 5 h after single oral dosesranging from 3 to 100 mg/kg 1. Av

7、agacestat (BMS-708163) (10mg/kg) monotherapy has a minor inhibitoryeffect on PC9/AB2 tumor growth compared with gefitinib alone. BMS-708163 monotherapy results in a slightincrease in caspase 3 expression as well as a mild decrease in Ki-67 expression in vivo. In the xenograftlung cancer samples trea

8、ted with Avagacestat (BMS-708163) plus gefitinib, there are a marked increase incaspase 3 expression and a reduction in Ki-67 staining 3.PROTOCOLCell Assay 3 The cell viability is assessed using a tetrazolium salt (WST-8)-based colorimetric assay from the CellCounting Kit 8 (CCK-8). The cells are se

9、eded into 96-well plates at an initial density of 5103 cells/well andcultured for 24h, after which the cells are cultured with DMSO, increased concentrations of gefitinib orAvagacestat (BMS-708163) , BIBW2992, or the combination of Avagacestat (BMS-708163) and BIBW2992for an additional 48h. The A450

10、 is measured in a microplate reader after 10L of CCK-8 solution is addedand incubated for 1h. The percentage of growth is shown relative to untreated controls.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Four- to six-week-old female Balb/c ath

11、ymic (nu+/nu+) mice are anesthetized with ether. The mice areAdministration 3 acclimatized for one week before being injected with 1.5106 PC9/AB2 cells that have been resuspended in200L of matrigel. When established tumors of approximately 150-300 mm3 in diameter are detected, themice are randomly d

12、ivided into groups and fed orally by gavage with either vehicle (1% methylcellulose, 0.2%Tween 80 in sterilized water), gefitinib (3mg/kg diluted in vehicle), Avagacestat (BMS-708163) (10mg/kg2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEdiluted in vehicle), or a combination of gefitinib (3mg/kg)

13、 and Avagacestat (BMS-708163) (10mg/kg) for 5days/week. Each treatment group consists of eight mice. The tumor volume are measured and calculatedevery five days using the following formula: /6(larger diameter)(smaller diameter)2. After 30 days, miceare killed by cervical dislocation.MCE has not inde

14、pendently 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) EMBO J. 2012 May 16;31(10):2261-74. J Alzheimers Dis. 2012;28(4):809-22.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Gillman KW, et al. Letter Discovery and Evaluation of BMS-708163, a

15、 Potent, Selective and Orally Bioavailable -Secretase Inhibitor.Med Chem Lett, 2010, 1 (3), 120-124.2. Crump CJ, et al. BMS-708,163 targets presenilin and lacks notch-sparing activity. Biochemistry. 2012 Sep 18;51(37):7209-11.3. Xie M, et al. Secretase inhibitor BMS-708163 reverses resistance to EGFR inhibitor via the PI3K/Akt pathway in lung cancer. J CellBiochem. 2015 Jun;116(6):1019-27.4. Borghys H, et al. A canine model to evaluate efficacy and safety of -secretase inhibitors and modulators.