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Research Area
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Description
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Solid tumours , Multiple myeloma, Lymphoma |
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Biological Activity
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Description
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MLN9708 is a selective inhibitor of chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM. |
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Targets
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20S proteasome |
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IC50 |
3.4 nM (IC50）, 0.93 nM（Ki) [1] |
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In Vitro
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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] |
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In Vivo
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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] |
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Clinical Trials
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MLN9708 is current under Phase II clinical trial in patients with relapsed multiple myeloma not refractory to bortezomib. |
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Features
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MLN9708 is first oral proteasome inhibitor in early stage clinical trials in Multiple Myeloma. |
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Protocol
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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. |
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Cell Assay
[1]
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| Cell Lines |
Calu-6 cells |
| Concentrations |
~10 nM |
| Incubation Time |
1 hour or 30 minutes |
| Methods |
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. |
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Animal Study
[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 |
| Doses |
11 mg/kg |
| Administration |
Twice weekly for 3 weeks (i.v.) |
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References |
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[1] Kupperman E, et al. Cancer Res, 2010, 70(5), 1970-80.
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[2] Chauhan D, et al. Clin Cancer Res, 2011, 17(16), 5311-21.
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[3] Lee EC, et al.Clin Cancer Res, 2011, 17(23),7313-23.
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[4] E. T. Rodler, et al. Journal of Clinical Oncology, 2010, 28(15)
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