Ixazomib Citrate (MLN9708) Analogue

CB-17 SCID mice are subcutaneously inoculated with MM.1S cells

4-(carboxymethyl)-2-((R)-1-(2-(2, 5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1, 3, 2-dioxaborinane-4-carboxylic acid

ca.10 nM

11 mg/kg

Dissolved in 5% 2-hydroxypropyl-beta-cyclodextrin

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]

1 hour or 30 minutes

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 uM 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.

MLN9708 Chemical Structure

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO