Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

• MeSH
• Alcoholism drug therapy   epidemiology   MeSH
• Molecular Targeted Therapy MeSH
• Disulfiram chemistry   pharmacology   therapeutic use   MeSH
• Adult MeSH
• Nuclear Proteins chemistry   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Copper chemistry   MeSH
• Mice MeSH
• Neoplasms drug therapy   metabolism   mortality   pathology   MeSH
• Alcohol Deterrents * pharmacology   therapeutic use   MeSH
• Drug Repositioning * MeSH
• Protein Aggregates MeSH
• Proteolysis drug effects   MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Heat-Shock Response drug effects   MeSH
• Protein Binding drug effects   MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Denmark epidemiology   MeSH
• Names of Substances
• Disulfiram MeSH
• Nuclear Proteins MeSH
• Copper MeSH
• NPLOC4 protein, human MeSH Browser
• Alcohol Deterrents * MeSH
• Protein Aggregates MeSH
• Antineoplastic Agents * MeSH

INTRODUCTION: Deubiquitinating-enzymes (DUBs) are key components of the ubiquitin-proteasome system (UPS). The fundamental role of DUBs is specific removal of ubiquitin from substrates. DUBs contribute to activation/deactivation, recycling and localization of numerous regulatory proteins, and thus play major roles in diverse cellular processes. Altered DUB activity is associated with a multitudes of pathologies including cancer. Therefore, DUBs represent novel candidates for target-directed drug development. AREAS COVERED: The article is a thorough review/accounting of patented compounds targeting DUBs and stratifying/classifying the patented compounds based on: chemical-structures, nucleic-acid compositions, modes-of-action, and targeting sites. The review provides a brief background on the UPS and the involvement of DUBs. Furthermore, methods for assessing efficacy and potential pharmacological utility of DUB inhibitor (DUBi) are discussed. EXPERT OPINION: The FDA's approval of the 20S proteasome inhibitors (PIs): bortezomib and carfilzomib for treatment of hematological malignancies established the UPS as an anti-cancer target. Unfortunately, many patients are inherently resistant or develop resistance to PIs. One potential strategy to combat PI resistance is targeting upstream components of the UPS such as DUBs. DUBs represent a promising potential therapeutic target due to their critical roles in various cellular processes including protein turnover, localization and cellular homeostasis. While considerable efforts have been undertaken to develop DUB modulators, significant advancements are necessary to move DUBis into the clinic.

• Keywords
• DUB inhibitors, cancer, deubiquitinating enzymes, drug discovery, molecular targeting, ubiquitin–proteasome system,
• MeSH
• Drug Resistance, Neoplasm MeSH
• Molecular Targeted Therapy MeSH
• Proteasome Inhibitors pharmacology   MeSH
• Humans MeSH
• Neoplasms drug therapy   enzymology   MeSH
• Patents as Topic MeSH
• Antineoplastic Agents pharmacology   MeSH
• Drug Design MeSH
• Ubiquitin-Specific Proteases antagonists & inhibitors   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Proteasome Inhibitors MeSH
• Antineoplastic Agents MeSH
• Ubiquitin-Specific Proteases MeSH