MLN9708 immediately hydrolyzed to MLN2238, which is an N-capped dipeptidyl leucine boronic acid and preferentially bound to and inhibited the 20S proteasome with an IC50 value of 3.4 nM (Ki = 0.93 nM).

In studies where a solution of MLN9708 was added directly into rat, dog, or human plasma and immediately extracted and analyzed by high-performance liquid chromatography, only MLN2238 could be identified. MLN2238 is an N-capped dipeptidyl leucine boronic acid and preferentially bound to and inhibited the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4nmol/L (Ki of 0.93nmol/L). At higher concentrations, it also inhibited the caspase-like (β1) and trypsin-like (β2) proteolytic sites (IC50 of 31 and 3,500 nmol/L, respectively). Treatment of MM cells with MLN2238 predominantly inhibits chymotrypsin-like activity of the proteasome and induces accumulation of ubiquitinated proteins. MLN2238 inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells. Overexpression of miR33b or MLN2238 exposure negatively regulated oncogene PIM-1 and blocked PIM-1 wild-type, but not PIM-1 mutant, luciferase activity. Moreover, PIM-1 overexpression led to significant abrogation of miR33b- or MLN2238-induced cell death.

Bortezomib  

Carfilzomib  

Delanzomib  

MG-132  

MLN2238  

ONX-0914  

Oprozomib  

PMSF