Ixazomib (MLN2238)

Catalog No.S2180

Ixazomib (MLN2238) Chemical Structure

Molecular Weight(MW): 361.03

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.

Size Price Stock Quantity  
In DMSO USD 250 In stock
USD 170 In stock
USD 320 In stock

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4 Customer Reviews

  • Primary myoblasts from patient 2 harboring a homozygous Arg555Trp DYSF mutation that were treated with the indicated amounts of MLN2238 for 24 hours.

    Sci Transl Med 2014 6(250), 250ra112. Ixazomib (MLN2238) purchased from Selleck.

    Other proteasome inhibitors that trigger Mcl-1128-350 generation and c-Jun upregulation. MM.1S cells were treated with carfilzomib (Carf), ixazomib (Ixaz), MG-132 (MG), or left untreated. After 24 h, total cell lysate was immunoblotted with Mcl-1, c-Jun and Tubulin.

    Cancer Lett 2014 343(2), 286-94. Ixazomib (MLN2238) purchased from Selleck.

  • Starved WT keratinocytes were treated without (lane 1) or with high calcium (lanes 2-5) in presence of indicated amount of proteasome inhibitor MLN2238 (lane 2-4) for 12 hrs as indicated. Cells were then subjected to immunoblotting analyses using anti-Ctip2 antibody. β-Actin, loading control. All experiments were performed in triplicates.

    J Cell Sci 2012 125(Pt 23), 5733-44. Ixazomib (MLN2238) purchased from Selleck.

    Nrf2 bound to ARE sequences was measured by immunoassay in nuclear extracts from K562 cells after treatment with tBHQ, bortezomib and MLN 2238.

    Hemoglobin 2014 38(3), 188-95. Ixazomib (MLN2238) purchased from Selleck.

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Biological Activity

Description 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.
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]

Protocol

Kinase Assay
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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
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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
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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 72 mg/mL (199.42 mM)
Ethanol 9 mg/mL (24.92 mM)
Water <1 mg/mL
In vivo 0.5% hydroxyethyl cellulose 30 mg/mL

* 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.

Chemical Information

Molecular Weight 361.03
Formula

C14H19BCl2N2O4

CAS No. 1072833-77-2
Storage powder
in solvent
Synonyms N/A

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID