MLN-2238 is a potent reversible and specific β5 site of the 20S proteasome inhibitor with an IC50 value of 3.4 nM. Proteasome activity was significantly inhibited in both blood and tumor following a single dose of MLN2238 administered IV at 14 mg/kg or SC at 4 mg/kg. Proteasome activity was inhibited greater than 50% for up to 8 hrs following the IV dose in both blood and tumor, whereas proteasome activity recovered more quickly following the SC dose. It is active in preclinical models of lymphoma, and that MLN2238 has antitumor activity in a model of lymphoma that is refractory to bortezomib treatment.