Ixazomib (MLN2238)

Catalog No.S2180 Batch:S218004

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Technical Data

Formula

C14H19BCl2N2O4
Molecular Weight 361.03 CAS No. 1072833-77-2
Solubility (25°C)* In vitro DMSO 72 mg/mL (199.42 mM)
Ethanol 72 mg/mL (199.42 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* 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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Ixazomib (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. Ixazomib (MLN2238) induces autophagy. Phase 3.
Targets
20S proteasome [1]
(Cell-free assay)		 20S proteasome [1]
(Cell-free assay)
0.93 nM(Ki) 3.4 nM
In vitro At higher concentrations, MLN2238 also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites with IC50 of 31nM and 3.5uM, respectively. MLN2238 inhibits Calu-6 cell with IC50 of 9.7 nM. MLN2238 is a selective, potent, and reversible inhibitor of the proteasome in tumor cells. MLN2238 shows time-dependent reversible proteasome inhibition. Both MLN2238 and Bortezomib shows time-dependent reversible proteasome inhibition; however, the proteasome dissociation half-life for MLN2238 is determined to be ∼6-fold faster than that of Bortezomib (18 and 110 minutes, respectively). MLN2238 dissociates more rapidly from the proteasome than Bortezomib, consistent with faster recovery of proteasome activity observed in the Proteasome-Glo assay. MLN2238 has a greater overall tumor pharmacodynamic effect than Bortezomib as assessed by 20S inhibition. [1]MLN2238 is the biologically active form of MLN9708. [2]
In vivo MLN2238 induces a greater pharmacodynamic response than Bortezomib in xenograft tumors. MLN2238 shows greater maximum and sustained tumor proteasome inhibition compared with Bortezomib in xenograft models. These results confirm that the improved tumor exposure seen with MLN2238 translates into an improved tumor pharmacodynamic response both at the level of and downstream from the proteasome. MLN2238 shows antitumor activity in the CWR22 xenograft model. MLN2238 shows greater tumor pharmacodynamic responses in WSU-DLCL2 xenografts compared with Bortezomib. Similarly, Bortezomib treatment only led to a minor increase in GADD34 levels in WSU-DLCL2 xenograft tumors, whereas MLN2238 strongly induces its expression. [1] MLN2238 has an improved pharmacodynamic profile and antitumor activity compared with Bortezomib in both OCI-Ly10 and PHTX22L models. [2]
Features A first-in-class proteasome inhibitor that has improved pharmacokinetics (PK), pharmacodynamics(PD), and antitumor activity in preclinical studies.

Protocol (from reference)

Kinase Assay:[1]
  • 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 Assay:[1]
  • 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.

Animal Study:[2]
  • Animal Models

    CB-17 SCID mice are subcutaneously inoculated with MM.1S cells

  • Dosages

    11 mg/kg

  • Administration

    Twice weekly for 3 weeks (i.v.)

Customer Product Validation

Data from [Data independently produced by Sci Transl Med, 2014, 6(250), 250ra112]

Data from [Data independently produced by Cancer Lett, 2014, 343(2), 286-94]

Data from [Data independently produced by Hemoglobin, 2014, 38(3), 188-95]

Data from [J Cell Sci, 2012, 125(Pt 23), 5733-44]

Selleck's Ixazomib (MLN2238) has been cited by 74 publications

Integrated transcriptomics- and structure-based drug repositioning identifies drugs with proteasome inhibitor properties [ Sci Rep, 2024, 14(1):18772] PubMed: 39138277
A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment [ Cell Rep Med, 2023, 10.1016/j.xcrm.2023.101286] PubMed: 37951217
Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors [ iScience, 2023, 26(8):107302] PubMed: 37554452
Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors [ iScience, 2023, 26(8):107302] PubMed: 37554452
Dual inhibition of HSF1 and DYRK2 impedes cancer progression [ Biosci Rep, 2023, 43(1)BSR20222102] PubMed: 36622366
Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans [ Microbiol Spectr, 2023, 11(5):e0190423] PubMed: 37750732
Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans [ Microbiol Spectr, 2023, 10.1128/spectrum.01904-23] PubMed: 37750732
S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes [ Cancer Res Commun, 2023, 3(3):420-430] PubMed: 36923707
S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes [ Cancer Res Commun, 2023, 3(3):420-430] PubMed: 36923707
Vactosertib, a novel TGF-β1 type I receptor kinase inhibitor, improves T-cell fitness: a single-arm, phase 1b trial in relapsed/refractory multiple myeloma [ Res Sq, 2023, rs.3.rs-3112163] PubMed: 37503043

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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