Cancer cells can be highly dependent on protein homeostasis pathways for their growth and survival. Here, Anderson et al. identify a potent and selective small-molecule inhibitor of p97 — a member of the AAA family of adenosine triphosphatases and a key regulator of protein homeostasis — named CB-5083. In cancer cells, CB-5083 blocked major protein-degradation functions, activating the unfolded protein response and apoptosis. CB-5083 significantly inhibited tumour growth in mouse haematological and solid tumour xenograft models and is currently in Phase I clinical trials.