Ixazomib (MLN2238)

Catalog No.S2180

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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Ixazomib (MLN2238) Chemical Structure

Ixazomib (MLN2238) Chemical Structure
Molecular Weight: 361.03

Validation & Quality Control

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Quality Control & MSDS

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Product Description

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.
Targets 20S proteasome [1]
(Cell-free assay)
20S proteasome [1]
(Cell-free assay)
IC50 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(Only for 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
Formulation Dissolved in 5% 2-hydroxypropyl-β-cyclodextrin
Dosages 11 mg/kg
Administration Twice weekly for 3 weeks (i.v.)

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Kupperman E, et al. Cancer Res, 2010, 70(5), 1970-80

[2] Lee EC, et al. Clin Cancer Res, 2011, 17(23), 7313-23.

Chemical Information

Download Ixazomib (MLN2238) SDF
Molecular Weight (MW) 361.03
Formula

C14H19BCl2N2O4

CAS No. 1072833-77-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 72 mg/mL (199.42 mM)
Ethanol 9 mg/mL (24.92 mM)
Water <1 mg/mL (<1 mM)
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 Name (R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutylboronic acid

Customer Product Validation(4)


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Rating
Source Sci Transl Med 2014 6(250), 250ra112. Ixazomib (MLN2238) purchased from Selleck
Method Western blot
Cell Lines Primary myoblasts
Concentrations 25, 50 nM
Incubation Time 24 h
Results To demonstrate that treatment with proteasome inhibitors other than bortezomib can also salvage missense mutated dysferlin, we treated primary myoblasts from patient 2 with MLN2238, which is the biologically active, hydrolyzed form of the investigational. MLN2238 was reported to have less neuropathic side effects as compared to bortezomib. It found that treatment with either of these newer-generation proteasome inhibitors resulted in a dose-dependent increase in dysferlin expression.

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Rating
Source Cancer Lett 2014 343(2), 286-94. Ixazomib (MLN2238) purchased from Selleck
Method Western blot
Cell Lines MM.1S cells
Concentrations 20, 40 nM
Incubation Time 24 h
Results The next generation proteasome-inhibitors carfilzomib and ixazomib, as well as the investigational proteasome inhibitor MG-132 also triggered generation of Mcl-1[128–350] and upregulation of c-Jun protein.

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Rating
Source J Cell Sci 2012 125(Pt 23), 5733-44. Ixazomib (MLN2238) purchased from Selleck
Method Western blot
Cell Lines keratinocytes
Concentrations 0-100 nM
Incubation Time 12 h
Results Treatment with proteasome inhibitor MLN2238 blocked degradation of endogenous Ctip2 by high calcium in a dose-dependent manner.

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Rating
Source Hemoglobin 2014 38(3), 188-95. Ixazomib (MLN2238) purchased from Selleck
Method Immunoassay
Cell Lines K562 cells
Concentrations 5, 25 nM
Incubation Time 18 h
Results K562 cells were treated with bortezomib and MLN 2238 (the active metabolite of the oral proteasome inhibitor MLN 9708) at concentrations of 5 and 25 nM for 18 hours. Nuclear Nrf2 was increased by 2.23-fold (range 1.1-3.9) and 1.63-fold (range 0.93-2.57) over control after treatment with 25 nM of bortezomib and MLN2238, respectively.

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