In agreement with this, approximately one third of single chromosomal aneu ploidies in yeast cells render them hypersensitive EPZ-5676 to proteasome inhibitors, and some yeast cells that adapted to aneuploidy were found to contain muta tions that derepress the UPS. These data suggest that agents that inhibit PQC pathways should be more toxic to cancer cells than normal cells, and might be used to treat a broad variety of cancers. In the remainder of this review, I will refer Inhibitors,Modulators,Libraries to this idea as the proteotoxic crisis approach to cancer therapy. Here, I will focus on tar geting PQC pathways of the UPS as a means to induce proteotoxic crisis in cancer cells. Other reviews have fo cused specifically on targeting chaperones or autophagy as a means to treat cancer.

Bortezomib validates the proteotoxic Inhibitors,Modulators,Libraries crisis hypothesis but raises questions about its generality The proteasome inhibitor bortezomib provided the first direct evidence that it is possible to inhibit the UPS in a manner that is lethal to at least some cancer cells while mostly sparing normal cells. Before discussing bor tezomib in detail, a primer on the structure and mech anism of the 26S proteasome is in order. The catalytic core of the proteasome is a 20S cylinder, the Inhibitors,Modulators,Libraries inside of which contains two copies Inhibitors,Modulators,Libraries each of the ac tive sites B1, B2, and B5. A second form of the proteasome, referred to as the immunoproteasome, is enriched in cells of the hematopoietic lineage and has a specialized function in immune cells, but an essentially analogous composition in which the B1, B2, and B5 sites are replaced by the closely related B1i, B2i, and B5i sites.

The Inhibitors,Modulators,Libraries B5 B5i sites are inhibited by bortezomib with high potency, whereas the B1 sites have approximately 10 fold lower affinity and the B2 sites are not appre ciably targeted under normal conditions. Substrates enter the 20S cylinder through its ends, which are capped with structures referred to as 19S regulatory particles. A 20S cylinder capped at each end with a 19S RP is referred to as the 26S proteasome. Assembly of the 26S proteasome is enabled by pockets at the ends of the 20S cylinder into which are inserted short carboxy terminal tails that emanate from a heterohexameric secondly ring of Rpt1 6 subunits in the 19S RP. Degradation substrates are teth ered to the 26S proteasome via their ubiquitin chain, which binds to one or more of a set of receptor proteins, some of which are in trinsic to the 19S RP, while others shuttle on and off.