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.

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In DMSO USD 250 In stock
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Cited by 21 Publications

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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]
Assay
Methods Test Index PMID
Western blot
PARP / Cleaved PARP / Caspase-3 / Cleaved Caspase-3 ; 

PubMed: 27687684     


(a-f) IMR-32 (a) NGP (b) NB-19 (c) SH-SY5Y (d) SK-N-AS (e) and LA-N-6 (f) cells were treated with 10 μM of ixazomib for various time points (0-24 hrs). The cells were then harvested at the end of the treatment, subjected to SDS-PAGE, and immunoblotted with PARP, Caspase-3, and β-actin primary antibodies. β-actin was used as a loading control for whole cell extracts in all samples.

Mcl-1 / Bcl-2 ; 

PubMed: 29348495     


Dose-dependent effects of MLN2238 treatment on Mcl-1 and Bcl-2 expression determined by western blot analysis. Cells exposed to the specified MLN2238 concentrations for 24 h.  

p53 / p21 / NOXA / PUMA / pRb / E2F / Cyclin D1 / CDK6 ; 

PubMed: 21724551     


(D and E) MM.1S cells were treated with MLN2238 (12 nM) for 24h and harvested; protein lysates were subjected to immunoblotting using indicated Abs. (F) MM.1R cells were treated with MLN2238 (12 nM) for 24h and harvested; protein lysates were subjected to immunoblotting using indicated Abs.

27687684 29348495 21724551
Growth inhibition assay
IC50; 

PubMed: 29416618     


The effect of ixazomib in a concentration-dependent manner for 72 h on viability of 28 representative DLBCL cell lines (10 non-GCB subtype and 18 GCB subtype) was assessed. The IC50 value for each cell line was calculated and plotted. * denotes double-hit DLBCL cell lines. 

29416618
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:[1]
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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:[1]
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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:[2]
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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 Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
5% DMSO+45% PEG 300+ddH2O
For best results, use promptly after mixing. 		17mg/mL

* 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