艾沙佐米作用機制 - Medchemexpress - MCE中國

1、Product Data SheetIxazomibCat. No.: HY-10453CAS No.: 1072833-77-2分式: CHBClNO分量: 361.03作靶點: Proteasome; Autophagy作通路: Metabolic Enzyme/Protease; Autophagy儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 28 mg/mL (77.56 mM)H2O : 0.1 mg/mL (insoluble)* means solubl

2、e, but saturation unknown.SolventMass1 mg 5 mg 10 mgConcentration制備儲備液1 mM 2.7699 mL 13.8493 mL 27.6985 mL5 mM 0.5540 mL 2.7699 mL 5.5397 mL10 mM 0.2770 mL 1.3849 mL 2.7699 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；旦配成溶液，請分裝保存，避免反復凍融造成的產(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在 6 個內(nèi)使，-20C 儲存時，請在

3、1 個內(nèi)使。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當?shù)娜芙獍?。以下溶解案都請先按?In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實驗結(jié)果的可靠性，澄 的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.92 mM); Clear solution此案可獲得 2.5 mg/mL

4、 (6.92 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.92 mM); Suspended solution; Need ultrasonicPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (6.92 m

5、M) 的均勻懸濁液，懸濁液可于服和腹腔注射。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻。3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.92 mM); Clear solution此案可獲得 2.5 mg/mL (6.92 mM，飽和度未知) 的澄 溶液，此案不適于實驗周 期在半個以上的實驗。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLO

6、GICAL 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，IC50 為 3.4 nM，Ki 為 0.93 nM。IC & Target IC50: 3.4 nM (20S proteasome)1Ki: 0.93 nM (20S proteasome)1體外研究 Ixazomib (MLN2238) is an N-capped dipeptidyl leucine boronic acid and preferentially bound to and inhibited

7、thechymotrypsin-like proteolytic (5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM). At higherconcentrations, Ixazomib (MLN2238) also inhibits the caspase-like (1) and trypsin-like (2) proteolytic sites (IC50 of31 and 3,500 nM, respectively). Cell viability studies are perfo

8、rmed in a variety of mammalian cell lines to compare thein vitro antiproliferative effects of Ixazomib (MLN2238) with Bortezomib. Studies performed with A375 (lung), H460(lung), HCT-116 (colon), and HT-29 (colon) cells revealed similar LD50 values for the two compounds, which rangefrom 4 to 58 nM1.體

9、內(nèi)研究 Ixazomib (MLN2238) shows antitumor activity in the CWR22 xenograft model. The antitumor effects of Ixazomib (MLN2238) dosed at 14 mg/kg i.v. or 7 mg/kg i.v. are compared with Bortezomib dosed at 0.8 mg/kg i.v. or 0.4 mg/kg i.v. on a twice weekly regimen. The high dose for both Ixazomib (MLN2238)

10、 and Bortezomib shows similar antitumoractivity in this model (T/C=0.36 and 0.44, respectively). However, Ixazomib (MLN2238) (7 mg/kg) shows greaterefficacy at a 0.5 MTD dose compared with a 0.5 MTD dose of Bortezomib (0.4 mg/kg; T/C=0.49 compared withT/C=0.79, respectively) Ixazomib (MLN2238) shows

11、 time-dependent reversible proteasome inhibition; however, theproteasome dissociation half-life (t1/2) for Ixazomib (MLN2238) is determined to be 18 minutes1.PROTOCOLCell Assay 1 Calu-6 cells are cultured in MEM containing 10% fetal bovine serum and 1% penicillin/streptomycin and plated 1 dbefore th

12、e start of the experiment at 10,000 cells per well in a 384-well plate. For IC50 determinations, cells aretreated with varying concentrations of Bortezomib or Ixazomib in DMSO (0.5% final, v/v) for 1 h at 37C. Forreversibility experiments, cells are treated with either 1 M Bortezomib or Ixazomib (ML

13、N2238) for 30 min at 37Cand then washed thrice in medium to remove the compounds. Cells are incubated for an additional 4 h at 37C, afterwhich the medium is removed and replaced with fresh medium. Proteasome activity is assessed by monitoringhydrolysis of the chymotrypsin-like substrate Suc-LLVY-ami

14、noluciferin in the presence of luciferase using theProteasome-Glo assay reagents. Luminescence is measured using a LEADseeker instrument1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice1Administration 1 Male CB17-SCID mice, approximately 8 t

15、o 11 wk of age, are inoculated s.c. with freshly dissected CWR22 tumorfragments (20 mg) in the right dorsal flank. Mean tumor volume (MTV) is calculated using the following formula:Page 2 of 3 www.MedChemE0.5(lengthwidth2). When MTV reaches approximately 150 to 200 mm3, animals are randomized into t

16、reatmentgroups (n=10 per group) before dosing. Antitumor activity is determined at the end of the study by calculating thetreatment over control (T/C) ratio of their MTVs at the end of the study.Rats1To determine the pharmacokinetic profile of Ixazomib and Bortezomib in a second species, Sprague-Daw

17、ley rats areadministered a single i.v. dose of Ixazomib (MLN2238) at either 0.3 or 0.2 mg/kg or Bortezomib at 0.2 mg/kg. BothIxazomib doses provided a greater plasma exposure (AUC0-48h of 704 and 1,070 hng/mL for 0.2 and 0.3 mg/kgdoses, respectively) compared with Bortezomib (AUC0-48h of 206 hng/mL)

18、, confirming that Ixazomib (MLN2238) alsohas improved plasma exposure compared with Bortezomib in rodents.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 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.MedChemE www.MedChemEREFERENCES1. Kupperman E, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical mo