Ixazomib-MLN2238-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEIxazomibCat. No.: HY-10453CAS No.: 1072833-77-2Synonyms: MLN2238分式: CHBClNO分量: 361.03作靶點(diǎn): Proteasome; Autophagy作通路: Metabolic Enzyme/Protease; Autophagy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

2、外實(shí)驗(yàn) DMSO : 28 mg/mL (77.56 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.92 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (6.92 mM); Suspended solution; Need ultrasonic3. 請依序添加每種溶劑： 10%

3、DMSO 90% corn oilSolubility: 2.5 mg/mL (6.92 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Ixazomib (MLN2238)種有效的選擇性的可逆蛋酶體 (proteasome)抑制劑，抑制20S蛋酶體的糜蛋酶樣蛋解 (5) 位點(diǎn)，IC50 為 3.4 nM，Ki 為 0.93 nM。IC50 & Target IC50: 3.4 nM (20S proteasome) 1Ki: 0.93 nM (20S proteasome) 1體外研究 Ixazomib (MLN2238) is an N-capped d

4、ipeptidyl leucine boronic acid and preferentially bound to and inhibitedthe chymotrypsin-like proteolytic (5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93nM). At higher concentrations, Ixazomib (MLN2238) also inhibits the caspase-like (1) and trypsin-like (2)proteolytic sites

5、(IC50 of 31 and 3,500 nM, respectively). Cell viability studies are performed in a variety ofmammalian cell lines to compare the in vitro antiproliferative effects of Ixazomib (MLN2238) with Bortezomib.Studies performed with A375 (lung), H460 (lung), HCT-116 (colon), and HT-29 (colon) cells revealed

6、 similarLD50 values for the two compounds, which range from 4 to 58 nM 1.體內(nèi)研究 Ixazomib (MLN2238) shows antitumor activity in the CWR22 xenograft model. The antitumor effects ofIxazomib (MLN2238) dosed at 14 mg/kg i.v. or 7 mg/kg i.v. are compared with Bortezomib dosed at 0.8mg/kg i.v. or 0.4 mg/kg i

7、.v. on a twice weekly regimen. The high dose for both Ixazomib (MLN2238) andBortezomib shows similar antitumor activity in this model (T/C=0.36 and 0.44, respectively). However,Ixazomib (MLN2238) (7 mg/kg) shows greater efficacy at a 0.5 MTD dose compared with a 0.5 MTD dose ofBortezomib (0.4 mg/kg;

8、 T/C=0.49 compared with T/C=0.79, respectively) Ixazomib (MLN2238) shows time-dependent reversible proteasome inhibition; however, the proteasome dissociation half-life (t1/2) for Ixazomib(MLN2238) is determined to be 18 minutes 1.PROTOCOLCell Assay 1 Calu-6 cells are cultured in MEM containing 10%

9、fetal bovine serum and 1% penicillin/streptomycin andplated 1 d before the start of the experiment at 10,000 cells per well in a 384-well plate. For IC50determinations, cells are treated with varying concentrations of Bortezomib or Ixazomib in DMSO (0.5% final,v/v) for 1 h at 37C. For reversibility

10、experiments, cells are treated with either 1 M Bortezomib or Ixazomib(MLN2238) for 30 min at 37C and then washed thrice in medium to remove the compounds. Cells areincubated for an additional 4 h at 37C, after which the medium is removed and replaced with fresh medium.Proteasome activity is assessed

11、 by monitoring hydrolysis of the chymotrypsin-like substrate Suc-LLVY-aminoluciferin in the presence of luciferase using the Proteasome-Glo assay reagents. Luminescence ismeasured using a LEADseeker instrument 1.MCE has not independently confirmed the accuracy of these methods. They are for referenc

12、e only.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEAnimal Mice 1Administration 1 Male CB17-SCID mice, approximately 8 to 11 wk of age, are inoculated s.c. with freshly dissected CWR22tumor fragments (20 mg) in the right dorsal flank. Mean tumor volume (MTV) is calculated using thefollowing form

13、ula: 0.5(lengthwidth2). When MTV reaches approximately 150 to 200 mm3, animals arerandomized into treatment groups (n=10 per group) before dosing. Antitumor activity is determined at the endof the study by calculating the treatment over control (T/C) ratio of their MTVs at the end of the study.Rats

14、1To determine the pharmacokinetic profile of Ixazomib and Bortezomib in a second species, Sprague-Dawleyrats are administered a single i.v. dose of Ixazomib (MLN2238) at either 0.3 or 0.2 mg/kg or Bortezomib at0.2 mg/kg. Both Ixazomib doses provided a greater plasma exposure (AUC0-48h of 704 and 1,0

15、70 hng/mLfor 0.2 and 0.3 mg/kg doses, respectively) compared with Bortezomib (AUC0-48h of 206 hng/mL),confirming that Ixazomib (MLN2238) also has improved plasma exposure compared with Bortezomib inrodents.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) Blood. 2019 Jan 10;133(2):156-167. Amyloid. 2019 Mar;26(1):24-33. bioRxiv. 2018 Dec.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Kupperman E, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cance