MLN9708

 Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

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

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

Customer Reviews (1)

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	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)

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  Linker for Activation of T-cell Family Member2 (LAT2) a Lipid Raft Adaptor Protein for AKT Signaling, Is an Early Mediator of Alkylphospholipid Anti-leukemic Activity. [Thomé CH, et al. Mol Cell Proteomics 2012;11(12):1898-912]