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Ixazomib citrate (MLN9708; MLN-9708; MLN 9708), the citrate salt and orally bioavailable prodrug of Ixazomib (MMLN2238; MMLN-2238), is a selective inhibitor of 20S proteasome (IC50 = 3.4 nM) with potential anticancer activity. It is being studied in various countries as a treatment for lymphoma, amyloidosis, and multiple myeloma in a Phase II trial. The boron-containing compound ixazomib citrate needs to be hydrolyzed to yield the pharmacologically active compound MLN2238 (ixazomib). Preclinical studies have shown that MLN9708 has better antitumor activity, pharmacokinetics, and pharmacodynamics than bortezomib.
| Targets |
20S proteasome β5 (IC50 = 3.4 nM); 20S proteasome β1 (IC50 = 31 nM); 20S proteasome β2 (IC50 = 3500 nM)
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|---|---|
| ln Vitro |
Ixazomib citrate (MLN9708; 0.20-3.20 μM) effectively suppresses the growth of both cell lines in a time- and dose-dependent manner. Cell cycle arrest is induced in MG-63 and Saos-2 cells by ixazomib. Ixazomib requires the activation of both caspase8 and caspase9 in order to induce apoptosis primarily through the caspases pathway. Treatment with ixazomib raises pro-apoptotic protein levels and decreases anti-apoptotic protein levels, which govern MOMP. Treatment with ixazomib causes the release of Cytc, Smac, and OMI from mitochondria and lowers XIAP protein levels. Ixazomib reduces MMP2/9 expression and secretion levels and inhibits the ability of MG-63 and Saos-2 cells to invade[1]. Ixazomib citrate (MLN9708; 12 nM) exhibits inhibitory action against the activities of the T-L and C-L proteasomes. Ixazomib treatment of H929 and MM.1S MM cells results in a notable increase in poly(ADP) ribose polymerase (PARP) proteolytic cleavage, a hallmark event during apoptosis. The upstream PARP activator caspase-3 is cleaved by isxazomib. Ixazomib increases the levels of CHOP/GADD153 and Bip protein as well as eIf2-α kinase activity. Ixazomib targets NF-κB, inhibits capillary tubule formation in vitro, and blocks MM cell proliferation induced by BMSCs[2].
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| ln Vivo |
Ixazomib citrate (MLN9708; 11 mg/kg) enhances survival in the human plasmacytoma MM.1S xenograft mouse model by substantially preventing the growth of MM tumors. Hemoglobin, bilirubin, and creatinine levels in the blood chemistry profiles of mice treated with ixazomib are normal. Cloned-caspase-3 positive cells in the xenograft model are significantly elevated by ixazomib[2].
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| Cell Assay |
The MTT assay is used to determine cell viability. Trypsinized cells are seeded at 5000 per well in 96-well plates. Ixazomib or DMSO are added to basal medium and given to the cells at the prescribed times and doses. The viability of the cells is assessed in relation to control cells that were given the vehicle alone.
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| Animal Protocol |
Ixazomib is dissolved at a concentration of 2 mg/mL in 5% 2-hydroxypropyl-β-cyclodextrin. The test makes use of a human plasmacytoma xenograft tumor model. After receiving a subcutaneous inoculation of 5.0×106 MM.1S cells in 100 µL serum-free RPMI-1640 medium, 21 CB-17 SCID mice are randomly assigned to treatment groups once their tumors have grown to a size of 250–300 mm3. For three weeks, mice are given vehicle, bortezomib (1 mg/kg; i.v.) or ixazomib (11 mg/kg; i.v.) twice a week. When a tumor grows to be 2 cm3, the animal is put to death.
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| References |
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| Molecular Formula |
C₂₀H₂₃BCL₂N₂O₉
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|---|---|
| Molecular Weight |
517.12
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| Exact Mass |
516.09
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| Elemental Analysis |
C, 46.45; H, 4.48; B, 2.09; Cl, 13.71; N, 5.42; O, 27.85
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| CAS # |
1239908-20-3
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| Related CAS # |
Ixazomib;1072833-77-2
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| Appearance |
White to off-white solid powder
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| SMILES |
B1(OC(=O)C(O1)(CC(=O)O)CC(=O)O)[C@H](CC(C)C)NC(=O)CNC(=O)C2=C(C=CC(=C2)Cl)Cl
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| InChi Key |
MBOMYENWWXQSNW-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C20H23BCl2N2O9/c1-10(2)5-14(21-33-19(32)20(34-21,7-16(27)28)8-17(29)30)25-15(26)9-24-18(31)12-6-11(22)3-4-13(12)23/h3-4,6,10,14H,5,7-9H2,1-2H3,(H,24,31)(H,25,26)(H,27,28)(H,29,30)/t14-/m0/s1
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| Chemical Name |
2-[4-(carboxymethyl)-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxaborolan-4-yl]acetic acid
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| Synonyms |
Ninlaro; MLN9708; MLN 9708; MLN-9708; ixazomib citrate; MMLN 2238-prodrug; MMLN-2238-prodrug; MMLN2238-prodrug; Ixazomib-prodrug
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 100~250 mg/mL (193.4~483.5 mM)
Ethanol: ~100 mg/mL (~193.4 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.02 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9338 mL | 9.6689 mL | 19.3379 mL | |
| 5 mM | 0.3868 mL | 1.9338 mL | 3.8676 mL | |
| 10 mM | 0.1934 mL | 0.9669 mL | 1.9338 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02181413 | Active Recruiting |
Drug: Ixazomib Citrate Drug: Placebo |
Multiple Myeloma Autologous Stem Cell Transplant |
Takeda | July 1, 2014 | Phase 3 |
| NCT02420847 | Active Recruiting |
Drug: Ixazomib Citrate Drug: Gemcitabine Hydrochloride |
Transitional Cell Carcinoma Metastatic Urothelial Carcinoma |
M.D. Anderson Cancer Center | July 3, 2015 | Phase 1 Phase 2 |
| NCT02339922 | Active Recruiting |
Drug: Ixazomib Citrate Biological: Rituximab |
Follicular Lymphoma Mantle Cell Lymphoma |
University of Washington | May 19, 2016 | Phase 2 |
| NCT02619682 | Active Recruiting |
Drug: Ixazomib Citrate Drug: Lenalidomide |
Transplant-Related Carcinoma Plasma Cell Myeloma |
Fred Hutchinson Cancer Center | December 30, 2015 | Phase 2 |
| NCT02633059 | Active Recruiting |
Drug: Ixazomib Citrate Drug: Idasanutlin |
Recurrent Plasma Cell Myeloma Loss of Chromosome 17p |
Mayo Clinic | December 30, 2015 | Phase 1 Phase 2 |
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