Ixazomib Citrate (MLN9708)
Molecular Weight(MW): 517.12
Ixazomib Citrate (MLN9708) immediately hydrolyzed to MLN2238, the biologically active form, on exposure to aqueous solutions or plasma. MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50/Ki of 3.4 nM/0.93 nM in cell-free assays, less potent to β1 and little activity to β2. Phase 3.
Cited by 6 Publications
3 Customer Reviews
LAT2 is degraded by proteasomes after treatment with alkylphospholipids. (A): 3-h treatment of NB4 cells before exposure to the proteasome inhibitor MG132 (10 M) prevented the reduction of LAT2 induced by 25 M ODPC. (B)(C): a similar effect was observed after exposure (30 min) of NB4 cells to the proteasome inhibitor MLN9708 (5 M) followed by treatment with 25 M ODPC (B) or 25 M perifosine (C).
Mol Cell Proteomics, 2012, 11(12): 1898-912. Ixazomib Citrate (MLN9708) purchased from Selleck.
Effect of proteasome inhibitors on [3H]-ryanodine binding. Panel A. Specific [3H]-ryanodine binding was measured in whole ventricle homogenates obtained in controls (C, white bars), after 30 min of ischemia (I, black bars) or after 30 min of ischemia followed by 60 minutes of reperfusion (IR, grey bars). MG132 was perfused at 0.5 μmol/L before ischemia (red bar, I) or from the very start of reperfusion (red bar, R). Values represent the mean ± S.E.M of different heartsas indicated in each bar *: p< 0.05 vs control or vs I + MG132. Panel B. Specific [3H]-ryanodine binding measured in hearts with the indicated concentration of ixazomib (ixa) perfused before ischemia. Values represent the mean ± S.E.M of values obtained in different hearts as indicated in each bar. *: p< 0.05 vs control
PLoS One, 2016, 11(8):e0161068. Ixazomib Citrate (MLN9708) purchased from Selleck.
Structure and IC50 determination of ixazomib. Results represent means of three independent biological replicates, error bars indicate standard deviations. Smears were stained using DiffQuik staining set, parasitemia was counted at 1000 RBCs. Statistical analysis was performed in R using ANOVA. * = p < 0.05, *** = p < 0.001 (compared to the DMSO treated culture). Experimental conditions: starting parasitemia 2% (dotted line), medium with inhibitory compounds exchanged in 12 h intervals, total cultivation duration 48 h. DC: DMSO treated culture (0.008%). UC: untreated culture. IC50: half maximal inhibitory concentration. RBCs: red blood cells.
Int J Parasitol Drugs Drug Resist, 2018, 8(3):394-402. Ixazomib Citrate (MLN9708) purchased from Selleck.
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Choose Selective Proteasome Inhibitors
|Description||Ixazomib Citrate (MLN9708) immediately hydrolyzed to MLN2238, the biologically active form, on exposure to aqueous solutions or plasma. MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50/Ki of 3.4 nM/0.93 nM in cell-free assays, less potent to β1 and little activity to β2. Phase 3.|
|Features||The 1st oral proteasome inhibitor in early stage clinical trials for Multiple Myeloma.|
MLN9708 is a selective, orally bioavailable, second-generation proteasome inhibitor. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib, which we believe plays an important role in its improved tissue distribution. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirms that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 is a second-generation small-molecule proteasome inhibitor being developed for the treatment of a broad range of human malignancies.  Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to its biologically active form MLN2238.  MLN2238 is the biologically active form of MLN9708. 
|In vivo||MLN9708 shows superior antitumor activity in both solid tumor and hematologic preclinical xenograft models when administered via multiple dosing routes and regimens.  Recent preclinical pharmacology studies shows that MLN9708 has a shorter proteasome dissociation half-life than bortezomib, as well as improved pharmacokinetics, pharmacodynamics, and antitumor activity in xenograft models  MLN9708 has shown antitumor efficacy in a wide range of tumor xenografts. |
Kinase assay:Calu-6 cells are cultured in MEM containing 10% fetal bovine serum and 1% penicillin/streptomycin and plated 1 day before the start of the experiment at 1 × 104 cells per well in a 384-well plate. Proteasome activity is assessed by monitoring hydrolysis of the chymotrypsin-like substrate Suc-LLVY-aminoluciferin in the presence of luciferase using the Proteasome-Glo assay reagents according to the manufacturer's instructions. Luminescence is measured using a LEADseeker instrument.
|In vitro||DMSO||100 mg/mL (193.37 mM)|
|In vivo||Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
0.5% hydroxyethyl cellulose
For best results, use promptly after mixing.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT03731832||Recruiting||Refractory Multiple Myeloma||GWT-TUD GmbH||September 20 2018||Phase 2|
|NCT03422874||Withdrawn||Neoplasms|Lymphoma||Dartmouth-Hitchcock Medical Center||August 2016||Phase 1|
|NCT02697383||Active not recruiting||Multiple Myeloma|High Risk Smoldering Multiple Myeloma||Memorial Sloan Kettering Cancer Center|Millennium Pharmaceuticals Inc.||February 2016||Phase 1|
|NCT02582359||Recruiting||Acute Myeloid Leukemia||Massachusetts General Hospital|Millennium Pharmaceuticals Inc.||January 2016||Phase 1|
|NCT02477215||Active not recruiting||Multiple Myeloma||Parameswaran Hari|Medical College of Wisconsin||October 9 2015||Phase 1|Phase 2|
|NCT02586038||Recruiting||Multiple Myeloma||Silvio Aime|University of Turin Italy||October 2015||Phase 2|
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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