MLN9708

Catalog No.S2181

MLN9708 Chemical Structure

Molecular Weight(MW): 517.12

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/Ki of 3.4 nM/0.93 nM in cell-free assays, less potent to β1 and little activity to β2. Phase 3.

Size Price Stock Quantity  
In DMSO USD 350 In stock
USD 170 In stock
USD 320 In stock
USD 970 In stock

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1 Customer Review

  • LAT2 is degraded by proteasomes after treatment with alkylphospholipids. (A): 3-h treatment of NB4 cells before exposure to the proteasome inhibitor MG132 (10 M) prevented the reduction of LAT2 induced by 25 M ODPC. (B)(C): a similar effect was observed after exposure (30 min) of NB4 cells to the proteasome inhibitor MLN9708 (5 M) followed by treatment with 25 M ODPC (B) or 25 M perifosine (C).

    Mol Cell Proteomics, 2012, 11(12): 1898-912. MLN9708 purchased from Selleck.

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Notes:

2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
4. Orange "√" refers to compounds which do inhibitory effects on the related isoform, but without specific value.

Biological Activity

Description 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/Ki of 3.4 nM/0.93 nM in cell-free assays, less potent to β1 and little activity to β2. Phase 3.
Features The 1st oral proteasome inhibitor in early stage clinical trials for Multiple Myeloma.
Targets
20S proteasome [1]
(Cell-free assay)
20S proteasome [1]
(Cell-free assay)
0.93 nM(Ki) 3.4 nM
In vitro

MLN9708 is a selective, orally bioavailable, second-generation proteasome inhibitor. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib, which we believe plays an important role in its improved tissue distribution. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirms that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 is a second-generation small-molecule proteasome inhibitor being developed for the treatment of a broad range of human malignancies. [1] Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to its biologically active form MLN2238. [2] MLN2238 is the biologically active form of MLN9708. [3]

In vivo MLN9708 shows superior antitumor activity in both solid tumor and hematologic preclinical xenograft models when administered via multiple dosing routes and regimens. [1] Recent preclinical pharmacology studies shows that MLN9708 has a shorter proteasome dissociation half-life than bortezomib, as well as improved pharmacokinetics, pharmacodynamics, and antitumor activity in xenograft models [2] MLN9708 has shown antitumor efficacy in a wide range of tumor xenografts. [4]

Protocol

Kinase Assay
+ 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
+ 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
+ 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)

Solubility (25°C)

In vitro DMSO 100 mg/mL (193.37 mM)
Water <1 mg/mL
Ethanol <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 517.12
Formula

C20H23BCl2N2O9

CAS No. 1201902-80-8
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02697383 Recruiting Multiple Myeloma|High Risk Smoldering Multiple Myeloma Memorial Sloan Kettering Cancer Center|Millennium Pharmaceuticals, Inc. February 2016 Phase 1
NCT02582359 Not yet recruiting Acute Myeloid Leukemia Massachusetts General Hospital|Millennium Pharmaceuticals, Inc. November 2015 Phase 1
NCT02586038 Recruiting Multiple Myeloma Silvio Aime|University of Turin, Italy October 2015 Phase 2
NCT02477215 Recruiting Multiple Myeloma Parameswaran Hari|Medical College of Wisconsin October 2015 Phase 1|Phase 2
NCT02384746 Recruiting Breast Cancer Dartmouth-Hitchcock Medical Center March 2015 Phase 1
NCT02228772 Recruiting Acute Lymphoblastic Leukemia|Lymphoblastic Lymphoma|B-cell Adult Acute Lymphoblastic Leukemia|T-cell Adult Acute Lymphoblastic Leukemia Massachusetts General Hospital|Millennium Pharmaceuticals, Inc. December 2014 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID