CB-5083 is an orally bioavailable inhibitor of p97 (IC50 = 11 nM), a transitional endoplasmic reticulum ATPase also known as valosin-containing protein (VCP). It disrupts cellular protein homeostasis and demonstrates anti-tumor activity in hematological and solid tumor models. CB-5083 causes accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and activation of the apoptotic arm of the unfolded protein response.