Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)

J Med Chem. 2015 Dec 24;58(24):9480-97. doi: 10.1021/acs.jmedchem.5b01346. Epub 2015 Dec 4.


The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin-proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. 71 has been taken into phase 1 clinical trials in patients with multiple myeloma and solid tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Biological Availability
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Female
  • Heterografts
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Mice, Nude
  • Molecular Docking Simulation
  • Neoplasm Transplantation
  • Nuclear Proteins / antagonists & inhibitors*
  • Proteasome Endopeptidase Complex / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Ubiquitin / metabolism
  • Unfolded Protein Response


  • Antineoplastic Agents
  • CB-5083
  • Indoles
  • Nuclear Proteins
  • Pyrimidines
  • Ubiquitin
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • p97 ATPase