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Purity: ≥98%
Ixazomib (formerly also known as MLN-2238) is a novel, potent, selective and reversible proteasome inhibitor (PI) with potential antineoplastic activity. It also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites, with IC50 of 31 and 3500 nM, respectively. In cell-free assays, it inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome. In both the OCI-Ly10 and PHTX22L models, MNL-2238, the biologically active form of MLN9708, exhibits better antitumor activity and a better pharmacodynamic profile than bortezomib.
| Targets |
20S proteasome (IC50 = 3.4 nM); 20S proteasome (Ki = 0.93 nM)
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| ln Vitro |
MLN2238 also inhibits the trypsin-like (β2) and caspase-like (β1) proteolytic sites at higher concentrations (IC50 = 3.5uM and 31nM, respectively). Calu-6 cell inhibition by MLN2238 has an IC50 of 9.7 nM. The proteasome in tumor cells is selectively, potently, and reversibly inhibited by MLN2238. Time-dependent reversible proteasome inhibition is demonstrated by MLN2238. Time-dependent reversible proteasome inhibition is demonstrated by both MLN2238 and Bortezomib; however, MLN2238's proteasome dissociation half-life is approximately six times faster than Bortezomib's (18 and 110 minutes, respectively). In line with the quicker recovery of proteasome activity seen in the Proteasome-Glo assay, MLN2238 dissociates from the proteasome more quickly than Bortezomib. 20S inhibition indicates that MLN2238 has a higher overall tumor pharmacodynamic effect than Bortezomib. (Source: ) The form of MLN9708 that is biologically active is MLN2238.[2]
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| ln Vivo |
MLN2238 causes xenograft tumors to respond more pharmacologically than Bortezomib. In comparison to Bortezomib, MLN2238 exhibits higher maximum and sustained tumor proteasome inhibition in xenograft models. These findings verify that enhanced tumor exposure observed with MLN2238 corresponds to an enhanced tumor pharmacodynamic response, both upstream and downstream of the proteasome. The CWR22 xenograft model demonstrates antitumor activity for MLN2238. In WSU-DLCL2 xenografts, MLN2238 exhibits higher tumor pharmacodynamic responses than boratezomib. Similarly, GADD34 expression is strongly induced by MLN2238, but Bortezomib treatment only slightly raised GADD34 levels in WSU-DLCL2 xenograft tumors.[1] In both the PHTX22L and OCI-Ly10 models, MLN2238 exhibits a better antitumor activity and pharmacodynamic profile than Bortezomib.[2]
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| Enzyme Assay |
One day prior to the commencement of the experiment, Calu-6 cells are plated at a density of 1 × 104 cells per well in a 384-well plate, grown in MEM supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. Using the Proteasome-Glo assay reagents in accordance with the manufacturer's instructions, proteasome activity is measured by tracking hydrolysis of the chymotrypsin-like substrate Suc-LLVY-aminoluciferin in the presence of luciferase. An apparatus called a LEADseeker is used to measure luminosity.
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| Cell Assay |
A day prior to the commencement of the experiment, 1 × 104 cells are plated in each well of a 384-well plate using Calu-6 cells that have been cultured in MEM supplemented with 10% FBS and 1% penicillin/streptomycin. Cells are treated for one hour at 37 °C with different doses of MLN2238 or boratezomib in 0.5% final v/v DMSO for IC50 calculations. To conduct reversibility tests, cells are exposed to 1 μM Bortezomib or MLN2238 for thirty minutes at 37 °C. Following treatment, the cells are triple-washed in medium to eliminate the Bortezomib or MLN2238. After four more hours of incubation at 37 °C, the medium is removed from the cells and replaced with new medium.
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| Animal Protocol |
Mice: Male CB17-SCID mice are injected subcutaneously (s.c.) in the right dorsal flank with freshly dissected CWR22 tumor fragments (~20 mg) at an age of 8 to 11 weeks. The formula to calculate the mean tumor volume (MTV) is 0.5×(length×width2). Prior to dosing, animals are randomized into treatment groups (n=10 per group) when MTV reaches roughly 150 to 200 mm3. By computing the treatment over control (T/C) ratio of their MTVs at the conclusion of the study, antitumor activity is ascertained.
Rats: Ixazomib (MLN2238) at 0.3 or 0.2 mg/kg or Bortezomib at 0.2 mg/kg is given intravenously (i.v.) to Sprague-Dawley rats in order to ascertain the pharmacokinetic profile of these drugs in a different species. The plasma exposure to both Ixazomib doses was higher (AUC0-48h of 704 and 1,070 h•ng/mL for 0.2 and 0.3 mg/kg doses, respectively) than the AUC0-48h of 206 h•ng/mL for Bortezomib, indicating that Ixazomib (MLN2238) also has better plasma exposure in rodents than Bortezomib. |
| References |
| Molecular Formula |
C14H19BCL2N2O4
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|---|---|
| Molecular Weight |
361.03
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| Exact Mass |
360.08
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| Elemental Analysis |
C, 46.58; H, 5.30; B, 2.99; Cl, 19.64; N, 7.76; O, 17.73
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| CAS # |
1072833-77-2
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| Related CAS # |
Ixazomib citrate;1239908-20-3
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| Appearance |
Solid powder
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| SMILES |
B([C@H](CC(C)C)NC(=O)CNC(=O)C1=C(C=CC(=C1)Cl)Cl)(O)O
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| InChi Key |
MXAYKZJJDUDWDS-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C14H19BCl2N2O4/c1-8(2)5-12(15(22)23)19-13(20)7-18-14(21)10-6-9(16)3-4-11(10)17/h3-4,6,8,12,22-23H,5,7H2,1-2H3,(H,18,21)(H,19,20)/t12-/m0/s1
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| Chemical Name |
[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid
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| Synonyms |
MLN-2238; MLN2238; IXAZOMIB; MLN 2238; Trade name: Ninlaro
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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) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7699 mL | 13.8493 mL | 27.6985 mL | |
| 5 mM | 0.5540 mL | 2.7699 mL | 5.5397 mL | |
| 10 mM | 0.2770 mL | 1.3849 mL | 2.7699 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 |
| NCT04837131 | Recruiting | Drug: Ixazomib | Scleroderma Systemic Sclerosis |
W. Leroy Griffing | April 28, 2021 | Phase 2 |
| NCT02924272 | Active Recruiting |
Drug: Ixazomib | Lymphoma Amyloidosis Disease |
Takeda | December 16, 2016 | Phase 2 |
| NCT03547700 | Active Recruiting |
Drug: Romidepsin Drug: Ixazomib |
Lymphoma, T-Cell, Peripheral | Ryan Wilcox | September 26, 2018 | Phase 1 Phase 2 |
| NCT03618537 | Recruiting | Drug: Ixazomib Drug: Dexamethasone |
AL Amyloidosis | Memorial Sloan Kettering Cancer Center |
August 2, 2018 | Phase 2 |
| NCT03748953 | Active Recruiting |
Drug: Ixazomib | Multiple Myeloma | Millennium Pharmaceuticals, Inc. | January 24, 2019 | Phase 3 |
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