Deubiquitinases (DUBs) and DUB inhibitors: a patent review

Abstract

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:

• cancer
• deubiquitinating enzymes
• drug discovery
• DUB inhibitors
• molecular targeting
• ubiquitin–proteasome system

Acknowledgments

P Farshi and RR Deshmukh contributed equally to this work.

Declaration of interest

This work was partially supported by NIH 1R01CA20009, 5R01CA127528-05, and NCI R21CA184788 (to QP Dou) and NSFC (81272451/H1609, 81472762/H1609) and MOE (20134423110002) (to J Liu). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

This box summarizes key points contained in the article.