The ubiquitin-proteasome system (UPS) is a conserved pathway regulating numerous 
biological processes including protein turnover, DNA repair, and intracellular 
trafficking. Tumor cells are dependent on a functioning UPS, making it an ideal 
target for the development of novel anti-cancer therapies. The development of 
bortezomib (Velcade(®)) as a treatment for multiple myeloma and mantle cell 
lymphoma has verified this and suggests that targeting other components of the 
UPS may be a viable strategy for the treatment for cancer. We recently described 
a novel class of proteasome inhibitors that function by an alternative mechanism 
of action (D'Arcy et al., 2011). The small molecule b-AP15 blocks the 
deubiquitinase (DUB) activity of the 19S regulatory particle (19S RP) without 
inhibiting the proteolytic activities of the 20S core particle (20S CP). b-AP15 
inhibits two proteasome-associated DUBs, USP14 and UCHL5, resulting in a rapid 
accumulation of high molecular weight ubiquitin conjugates and a functional 
proteasome shutdown. Interestingly, b-AP15 displays several differences to 
bortezomib including insensitivity to over-expression of the anti-apoptotic 
mediator Bcl-2 and anti-tumor activity in solid tumor models. In this review we 
will discuss the potential of proteasome deubiquitinase inhibitors as additions 
to the therapeutic arsenal against cancer.