Definition

The tosylate salt of CB-5339, an orally bioavailable, selective, second-generation inhibitor of valosin-containing protein (VCP)/p97, with potential antineoplastic activity. Upon oral administration, p97 inhibitor CB-5339 binds to and inhibits the activity of p97. This prevents ubiquitin-dependent protein degradation and causes cellular accumulation of poly-ubiquitinated proteins. The inhibition of endoplasmic reticulum (ER)-associated protein degradation activates the ER-dependent stress response pathway, and leads to both an induction of apoptosis and the inhibition of cell proliferation in susceptible tumor cells. VCP/p97, a type II AAA+ ATPase, plays a key role in cellular protein homeostasis processes including endoplasmic reticulum associated degradation (ERAD), chromatin associated degradation (CAD) and the DNA damage response (DDR). Its overexpression in many tumor cell types is associated with increased tumor cell proliferation and survival.