p97 Inhibitor 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 ER-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.