MLN9708

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, less potent to β1 and little activity to β2. Phase 3.

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MLN9708 Chemical Structure

MLN9708 Chemical Structure
Molecular Weight: 517.12

Validation & Quality Control

Customer Reviews(1)

Quality Control & MSDS

Related Compound Libraries

MLN9708 is available in the following compound libraries:

Product Information

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Product Description

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, less potent to β1 and little activity to β2. Phase 3.
Targets 20S proteasome
IC50 3.4 nM (IC50), 0.93 nM(Ki) [1]
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]
Features The 1st oral proteasome inhibitor in early stage clinical trials for Multiple Myeloma.

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
Dosages 11 mg/kg
Administration Twice weekly for 3 weeks (i.v.)
Solubility 0.5% hyroxyethylcellulose., 30 mg/mL
1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01645930 Recruiting Multiple Myeloma Millennium Pharmaceuticals, Inc. 2012-12 Phase 1
NCT01718743 Recruiting Myeloma M.D. Anderson Cancer Center|Millennium Pharmaceuticals, Inc. 2012-12 Phase 1
NCT01830816 Recruiting Multiple Myeloma Millennium Pharmaceuticals, Inc. 2013-05 Phase 1
NCT01850524 Recruiting Multiple Myeloma Millennium Pharmaceuticals, Inc. 2013-05 Phase 3
NCT01864018 Not yet recruiting Stage I Multiple Myeloma|Stage II Multiple Myeloma|Stage III Multiple Myeloma Mayo Clinic|National Cancer Institute (NCI) 2013-07 Phase 1|Phase 2

Chemical Information

Download MLN9708 SDF
Molecular Weight (MW) 517.12
Formula

C20H23BCl2N2O9

CAS No. 1201902-80-8
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Syonnyms N/A
Solubility (25°C) * In vitro DMSO 103 mg/mL (199 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% hyroxyethylcellulose., 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 4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid

Preparing Stock Solutions

Stock Solution (1ml DMSO) 1mM 10mM 20mM 30mM
Mass(mg) 0.51712 5.1712 10.3424 15.5136

Research Area

Customer Reviews (1)


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Rating
Source Mol Cell Proteomics, 2012, 11(12), 1898-1912 . MLN9708 purchased from Selleck
Method Western Blot
Cell Lines NB4 cells
Concentrations 5 μM
Incubation Time 30 min
Results In these experiments, the presence of MLN9708 caused an accumulation of LAT2 after ODPC (Fig. B)or perifosine (Fig. C) treatment, confirming that LAT2 is degraded by proteasomes after treatment with APL.

Product Citations (1)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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  • MLN9708

    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, 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.

  • MLN2238

    MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM, respectively, also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites, with IC50 of 31 and 3500 nM.

    Features:A first-in-class proteasome inhibitor that has improved pharmacokinetics (PK), pharmacodynamics(PD), and antitumor activity in preclinical studies.

  • CEP-18770 (Delanzomib)

    CEP-18770 is an orally active inhibitor of the chymotrypsin-like activity of proteasome with IC50 of 3.8 nM, with only marginal inhibition of the tryptic and peptidylglutamyl activities of the proteosome. Phase 1/2.

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