Ixazomib (MLN2238)

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

(R)-1-(2-(2, 5-dichlorobenzamido)acetamido)-3-methylbutylboronic acid

ca.10 nM

11 mg/kg

Dissolved in 5% 2-hydroxypropyl-beta-cyclodextrin

At higher concentrations, MLN2238 also inhibits the caspase-like (beta1) and trypsin-like (beta2) proteolytic sites with IC50 of 31nM and 3.5uM, respectively. MLN2238 inhibits Calu-6 cell with IC50 of 9.7 nM. MLN2238 is a selective, potent, and reversible inhibitor of the proteasome in tumor cells. MLN2238 shows time-dependent reversible proteasome inhibition. Both MLN2238 and Bortezomib shows time-dependent reversible proteasome inhibition, however, the proteasome dissociation half-life for MLN2238 is determined to be 6-fold faster than that of Bortezomib (18 and 110 minutes, respectively). MLN2238 dissociates more rapidly from the proteasome than Bortezomib, consistent with faster recovery of proteasome activity observed in the Proteasome-Glo assay. MLN2238 has a greater overall tumor pharmacodynamic effect than Bortezomib as assessed by 20S inhibition. [1]MLN2238 is the biologically active form of MLN9708. [2]

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.

MLN2238 Chemical Structure

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