Development of novel cancer therapy based on inhibition of the ubiquitin-proteasome system.
Tumor cells display enhanced sensitivity to disruptions in the ubiquitin-proteasome system UPS) making this an attractive target for the development of anti-cancer therapies. Ubiquitin-tagged substrates are degraded by the 26S proteasome; a multisubunit complex comprising a proteolytic 20S core particle (20S CP) capped by 19S regulatory particles (19S RP). The 20S CP has evolved as an important target for anti-cancer drug development, resulting in the approval of bortezomib (Velcade®) for the treatment of multiple myeloma. We have identified the small molecule b-AP15 as a novel class of proteasome inhibitor that functions by abrogating the deubiquitinating (DUB) activity of the 19S RP (D’Arcy et al., Nature Medicine 2011). b-AP15 inhibits the activity of two 19S RP-associated DUBs, UCHL5 and USP14. Consistent with DUB inhibition, treatment with b-AP15 caused the accumulation of polyubiquitinated proteins with higher molecular weight compared to bortezomib treatment and induced a stronger proteotoxic response. Importantly, apoptosis induction by b-AP15 differed from that of bortezomib by being insensitive to disruptions of the p53 tumor suppressor and insensitive to overexpression of the intrinsic apoptotic suppressor Bcl-2. b-AP15 shows strong activity on multiple myeloma models (Tian et al.., Blood 2014) and clinical trials are planned for this disease. Our results suggest that inhibiting the DUB activity of the 19S RP may be a novel target for the treatment of cancer.