Ixazomib Citrate (MLN9708)

For research use only. Not for use in humans.

Catalog No.S2181

11 publications

Ixazomib Citrate (MLN9708) Chemical Structure

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.

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Selleck's Ixazomib Citrate (MLN9708) has been cited by 11 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.

Purity & Quality Control

Choose Selective Proteasome Inhibitors

Biological Activity

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.
Targets
20S proteasome [1]
(Cell-free assay)		 20S proteasome [1]
(Cell-free assay)
0.93 nM(Ki) 3.4 nM
In vitro

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. [1] Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to its biologically active form MLN2238. [2] MLN2238 is the biologically active form of MLN9708. [3]
Assay
Methods Test Index PMID
Western blot
PARP / Cleaved PARP / Caspase-3 / Cleaved Caspase-3 ; 

PubMed: 27687684     


(a-f) IMR-32 (a) NGP (b) NB-19 (c) SH-SY5Y (d) SK-N-AS (e) and LA-N-6 (f) cells were treated with 10 μM of ixazomib for various time points (0-24 hrs). The cells were then harvested at the end of the treatment, subjected to SDS-PAGE, and immunoblotted with PARP, Caspase-3, and β-actin primary antibodies. β-actin was used as a loading control for whole cell extracts in all samples.

Mcl-1 / Bcl-2 ; 

PubMed: 29348495     


Dose-dependent effects of MLN2238 treatment on Mcl-1 and Bcl-2 expression determined by western blot analysis. Cells exposed to the specified MLN2238 concentrations for 24 h.  

p53 / p21 / NOXA / PUMA / pRb / E2F / Cyclin D1 / CDK6 ; 

PubMed: 21724551     


(D and E) MM.1S cells were treated with MLN2238 (12 nM) for 24h and harvested; protein lysates were subjected to immunoblotting using indicated Abs. (F) MM.1R cells were treated with MLN2238 (12 nM) for 24h and harvested; protein lysates were subjected to immunoblotting using indicated Abs.

27687684 29348495 21724551
Growth inhibition assay
IC50; 

PubMed: 29416618     


The effect of ixazomib in a concentration-dependent manner for 72 h on viability of 28 representative DLBCL cell lines (10 non-GCB subtype and 18 GCB subtype) was assessed. The IC50 value for each cell line was calculated and plotted. * denotes double-hit DLBCL cell lines. 

29416618
In vivo MLN9708 shows superior antitumor activity in both solid tumor and hematologic preclinical xenograft models when administered via multiple dosing routes and regimens. [1] 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 [2] MLN9708 has shown antitumor efficacy in a wide range of tumor xenografts. [4]

Protocol

Kinase Assay:[1]
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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.
Cell Research:[1]
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  • Cell lines: Calu-6 cells
  • Concentrations: ~10 nM
  • Incubation Time: 1 hour or 30 minutes
  • Method: Calu-6 cells are cultured in MEM containing 10% FBS 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. For IC50 determinations, cells are treated with varying concentrations of Bortezomib or MLN2238 in DMSO (0.5% final, v/v) for 1 hour at 37 °C. For reversibility experiments, cells are treated with either 1 μM Bortezomib or MLN2238 for 30 minutes at 37 °C and then washed thrice in medium to remove the Bortezomib or MLN2238. Cells are incubated for an additional 4 hours at 37 °C, after which the medium is removed and replaced with fresh medium.
    (Only for Reference)
Animal Research:[2]
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  • Animal Models: CB-17 SCID mice are subcutaneously inoculated with MM.1S cells
  • Formulation: Dissolved in 5% 2-hydroxypropyl-β-cyclodextrin
  • Dosages: 11 mg/kg
  • Administration: Twice weekly for 3 weeks (i.v.)
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (193.37 mM)
Water Insoluble
Ethanol Insoluble
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. 		30 mg/mL

* 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.

Chemical Information

Molecular Weight 517.12
Formula

C20H23BCl2N2O9
CAS No. 1201902-80-8
Storage powder
in solvent
Synonyms N/A
Smiles CC(C)CC(NC(=O)CNC(=O)C1=C(Cl)C=CC(=C1)Cl)B2OC(=O)CC(CC(O)=O)(O2)C(O)=O

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03422874 Withdrawn Drug: MLN9708|Drug: Nelfinavir Neoplasms|Lymphoma Dartmouth-Hitchcock Medical Center August 2016 Phase 1
NCT02582359 Recruiting Drug: MLN9708|Drug: Cytarabine|Drug: Daunorubicin Acute Myeloid Leukemia Massachusetts General Hospital|Millennium Pharmaceuticals Inc. January 2016 Phase 1
NCT02477215 Active not recruiting Drug: MLN9708|Drug: Dexamethasone|Drug: Bendamustine Multiple Myeloma Parameswaran Hari|Medical College of Wisconsin October 9 2015 Phase 1|Phase 2
NCT02250300 Active not recruiting Drug: MLN9708 Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation Mehdi Hamadani|Medical College of Wisconsin November 2014 Phase 1|Phase 2
NCT01936532 Active not recruiting Drug: MLN9708|Drug: Lenalidomide|Drug: Dexamethasone Newly Diagnosed Multiple Myeloma Nantes University Hospital November 12 2014 Phase 2

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Proteasome Signaling Pathway Map

Proteasome Inhibitors with Unique Features

  • Pan Proteasome Inhibitor

    Ixazomib (MLN2238) : β5 site, IC50=3.4 nM; β1 site, IC50=31 nM; β2 site, IC50=3500 nM.

  • FDA-approved Proteasome Inhibitor

    Carfilzomib (PR-171) : Approved by FDA for multiple myeloma.

  • Newest Proteasome Inhibitor

    Oprozomib (ONX 0912) : Orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM.

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  • MG-132

    MG132 is a potent cell-permeable proteasome and calpain inhibitor with IC50s of 0.1 and 1.2 μM for the inhibition of proteasome and calpain, respectively.

  • Bortezomib (PS-341)

    Bortezomib (PS-341) is a potent 20S proteasome inhibitor with Ki of 0.6 nM. It exhibits favorable selectivity towards tumor cells over normal cells.

  • Carfilzomib (PR-171)

    Carfilzomib (PR-171) is an irreversible proteasome inhibitor with IC50 of <5 nM in ANBL-6 cells, displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, but little or no effect on the PGPH and T-L activities.

  • Ixazomib (MLN2238)

    MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM in cell-free assays, respectively, also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites, with IC50 of 31 and 3500 nM. Phase 3.

    Features:A first-in-class proteasome inhibitor that has improved pharmacokinetics (PK), pharmacodynamics(PD), and antitumor activity in preclinical studies.

  • Celastrol

    Celastrol is a potent proteasome inhibitor for the chymotrypsin-like activity of a purified 20S proteasome with IC50 of 2.5 μM.

    Features:A potent antioxidant and anti-inflammatory drug.

  • Oprozomib (ONX 0912)

    Oprozomib (ONX 0912) is an orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM. Phase 1/2.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID