Ixazomib (MLN2238)

Catalog No.S2180

Molecular Weight(MW): 361.03

MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and K_i 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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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-1^128-350 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.

Ixazomib is a slow-binding competitive inhibitor of the 20S proteasome. (A) Plot of the initial phase velocity v0 for the 20S proteasome-catalyzed hydrolysis of Suc-LLVYAMC determined over 2 min directly after the addition of varying concentrations of ixazomib to the assay mixture. The initial velocity was essentially unchanged at ixazomib concentrations up to 15 nM, which indicates that ixazomib did not competitively inhibit the 20S proteasome in a rapid pre-equilibrium binding reaction, at least over this concentration range. The straight line was linear-least squares calculated and has a SE about equal to the value of the slope. (B) Plot of the final phase velocity vS for the 20S proteasome-catalyzed hydrolysis of Suc-LLVY-AMC calculated from curve fitting of progress curves to an equation for slow-binding kinetics. The curved line was nonlinear-least squares calculated from fitting a two-parameter saturation equation (Eq. (4)) for KI yielded a KI of 4.9 ± 0.4 nM, consistent with ixazomib being a slow-binding competitive inhibitor of the 20S proteasome.

Arch Biochem Biophys, 2018, 639:52-58. 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

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:^[1]	+ Expand 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]	+ Expand 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]	+ Expand 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)

References

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 Download Ixazomib (MLN2238) SDF

Molecular Weight	361.03
Formula	C₁₄H₁₉BCl₂N₂O₄
CAS No.	1072833-77-2
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	N/A

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Ixazomib Citrate (MLN9708)

Ixazomib Citrate (MLN9708) immediately hydrolyzed to MLN2238, the biologically active form, on exposure to aqueous solutions or plasma. MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50/K_i of 3.4 nM/0.93 nM in cell-free assays, less potent to β1 and little activity to β2. Phase 3.

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Ixazomib (MLN2238)