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, thus playing major roles in diverse cellular-processes. Altered DUB activity is associated with 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 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 DUBs involvement. 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: 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 proteasome inhibitors (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 advancement is necessary move DUB inhibitors into the clinic.

The Emerging Role of Non-traditional Ubiquitination in Oncogenic Pathways

“…The inhibition of E3 ligases may be one of the most attractive approaches, as these enzymes target a limited number of substrates and contain an enzymatic catalytic site for which a small molecule inhibitor can be specifically designed (80). DUB inhibition is also an emerging area of interest, with many large pharmaceutical companies now investing in this class of drugs (81). Several DUBs have been described as key players in tumorigenesis, and as cysteine proteases, they also represent a very "druggable" class of proteins (38).…”

The role of K63‐linked polyubiquitination in cardiac hypertrophy

“…Due to their role in proteostasis, they have fundamental role in both normal and pathogenic cellular processes 37, 38, 39. Most strikingly, recent evidence indicates that the dysregulation of DUB function is closely associated with several diseases, including cancer and heart diseases 40, 41, 42…”

Regulation of pluripotency and differentiation by deubiquitinating enzymes

“…In addition, recent advances in small-molecule-based inhibitors specifically targeting DUBs also make DUBs attractive therapeutic targets for antiviral and anticancer agents. [82][83][84] Several DUBs are directly or indirectly involved in downregulating or ablating oncogene products or, alternatively, upregulating or suppressing tumor suppressors (reviewed in Lim and Baek, 85 Pal and Donato 86 ). Some specific examples of DUBs that are viable targets for anticancer therapy include USP2, USP4, USP7, USP9X, USP11, and USP15.…”

“…103 Along with cancer, the applicability of DUB inhibitors is being examined in other therapeutic areas including neurodegeneration and infectious disease. 82,83,104,105 Several partial and specific inhibitors against USPs have been developed and utilized in research. So far, many DUB inhibitors have been found to be effective against USP family members such as USP1, USP2, USP5, USP7, USP8, USP9x, USP10, USP11, USP13, USP14, USP20, USP30, and USP37, as well as UCH family members such as UCHL1, UCHL3, and UCHL5.…”

“…So far, many DUB inhibitors have been found to be effective against USP family members such as USP1, USP2, USP5, USP7, USP8, USP9x, USP10, USP11, USP13, USP14, USP20, USP30, and USP37, as well as UCH family members such as UCHL1, UCHL3, and UCHL5. [82][83][84] The tumor suppressor p53 acts as a master regulator of stem cell and iPSC differentiation in response to genomic damage. [106][107][108] Thus, targeting DUBs specific to p53 might be an alternative method to regulate stem cell differentiation.…”