The Efficacy of a Novel Oral Proteasome Inhibitor NNU546 in Multiple Myeloma

Proteasome inhibition demonstrates highly effective impact on multiple myeloma (MM) treatment. In this study we aimed to examine a novel well tolerated orally applicable proteasome inhibitor NNU546 and its hydrolyzed pharmacologically active form NNU219. NNU219 showed more selective inhibition to proteasome catalytic subunits and less off-target effect than bortezomib ex vivo. Furthermore, intravenous and oral administration of NNU219 and NNU546, respectively, led to a more sustained pharmacodynamic inhibition of proteasome activities compared with bortezomib. Intriguingly, NNU219 exhibited potential anti-MM activity on both MM cell lines and primary samples in vitro. The anti-MM activity of NNU219 was determined to be associated with induction of G2/M-phase arrest, as well as induction of apoptosis via activation of the caspase cascade and endoplasmic reticulum stress response. At well-tolerated doses, significant growth-inhibitory effects of NNU219 and NNU546 were observed in 3 different human MM xenograft mouse models and significant anti-MM activity was observed even in the presence of a bone marrow microenvironment. Taken together, these findings provided the basis for clinical trials of NNU546 to determine its potential as a candidate for MM treatment.