1. Metabolic Enzyme/Protease
    Autophagy
  2. Proteasome
    Autophagy

MLN2238 (Synonyms: Ixazomib)

Cat. No.: HY-10453 Purity: 99.07%
Handling Instructions

MLN2238 is a selective, potent, and reversible proteasome inhibitor, which inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM).

For research use only. We do not sell to patients.
MLN2238 Chemical Structure

MLN2238 Chemical Structure

CAS No. : 1072833-77-2

Size Price Stock Quantity
10 mM * 1 mL in DMSO USD 119 In-stock
5 mg USD 108 In-stock
10 mg USD 144 In-stock
25 mg USD 324 In-stock
50 mg USD 540 In-stock
100 mg   Get quote  
200 mg   Get quote  

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  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

MLN2238 is a selective, potent, and reversible proteasome inhibitor, which inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM).

IC50 & Target

IC50: 3.4 nM (20S proteasome)[1]
Ki: 0.93 nM (20S proteasome)[1]

In Vitro

MLN2238 is an N-capped dipeptidyl leucine boronic acid and preferentially bound to and inhibited the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM). At higher concentrations, MLN2238 also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites (IC50 of 31 and 3,500 nM, respectively). Cell viability studies are performed in a variety of mammalian cell lines to compare the in vitro antiproliferative effects of MLN2238 with Bortezomib. Studies performed with A375 (lung), H460 (lung), HCT-116 (colon), and HT-29 (colon) cells revealed similar LD50 values for the two compounds, which range from 4 to 58 nM[1].

In Vivo

MLN2238 shows antitumor activity in the CWR22 xenograft model. The antitumor effects of MLN2238 dosed at 14 mg/kg i.v. or 7 mg/kg i.v. are compared with Bortezomib dosed at 0.8 mg/kg i.v. or 0.4 mg/kg i.v. on a twice weekly regimen. The high dose for both MLN2238 and Bortezomib shows similar antitumor activity in this model (T/C=0.36 and 0.44, respectively). However, MLN2238 (7 mg/kg) shows greater efficacy at a 0.5 MTD dose compared with a 0.5 MTD dose of Bortezomib (0.4 mg/kg; T/C=0.49 compared with T/C=0.79, respectively) MLN2238 shows time-dependent reversible proteasome inhibition; however, the proteasome dissociation half-life (t1/2) for MLN2238 is determined to be 18 minutes[1].

Clinical Trial
References
Preparing Stock Solutions
Concentration Volume Mass 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
Please refer to the solubility information to select the appropriate solvent.
Cell Assay
[1]

MLN2238 is dissolved in DMSO and then diluted with appropriate media[1].

Calu-6 cells are cultured in MEM containing 10% fetal bovine serum and 1% penicillin/streptomycin and plated 1 d before the start of the experiment at 10,000 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 h at 37°C. For reversibility experiments, cells are treated with either 1 μM Bortezomib or MLN2238 for 30 min at 37°C and then washed thrice in medium to remove the compounds. Cells are incubated for an additional 4 h at 37°C, after which the medium is removed and replaced with fresh medium. 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. Luminescence is measured using a LEADseeker instrument[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

MLN2238 is prepared in 5% HPβCD[1].

Mice[1]
Male CB17-SCID mice, approximately 8 to 11 wk of age, are inoculated s.c. with freshly dissected CWR22 tumor fragments (~20 mg) in the right dorsal flank. Mean tumor volume (MTV) is calculated using the following formula: 0.5×(length×width2). When MTV reaches approximately 150 to 200 mm3, animals are randomized into treatment groups (n=10 per group) before dosing. Antitumor activity is determined at the end of the study by calculating the treatment over control (T/C) ratio of their MTVs at the end of the study.
Rats[1]
To determine the pharmacokinetic profile of MLN2238 and Bortezomib in a second species, Sprague-Dawley rats are administered a single i.v. dose of MLN2238 at either 0.3 or 0.2 mg/kg or Bortezomib at 0.2 mg/kg. Both MLN2238 doses provided a greater plasma exposure (AUC0-48h of 704 and 1,070 h•ng/mL for 0.2 and 0.3 mg/kg doses, respectively) compared with Bortezomib (AUC0-48h of 206 h•ng/mL), confirming that MLN2238 also has improved plasma exposure compared with Bortezomib in rodents. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

361.03

Formula

C₁₄H₁₉BCl₂N₂O₄

CAS No.

1072833-77-2

SMILES

CC(C)C[[email protected]@H](B(O)O)NC(CNC(C1=CC(Cl)=CC=C1Cl)=O)=O

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 28 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.07%

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MLN2238
Cat. No.:
HY-10453
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