Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors

Kemp, Mark I.

doi:10.1016/bs.pmch.2015.10.002

Cited by 67 publications

(70 citation statements)

References 116 publications

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“…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.…”

Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

“…Although there are strong similarities within the active-site cysteine and histidine boxes of several DUBs, the three-dimensional structure of each DUB has unique differences in accessibility to the catalytic pocket. 83 Since the approval of the proteasome inhibitors bortezomib and carfilzomib for the treatment of hematological malignancies, 102 there has been great interest in targeting the deubiquitination process upstream of the proteasome in cancer therapy. Auronofin (Aur) is an inhibitor of the proteasome-associated deubiquitinases UCHL5 and USP14, but not the 20S proteasome, that leads to Aur-induced cytotoxicity.…”

Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

“…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.…”

Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

“…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.…”

Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

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Regulation of pluripotency and differentiation by deubiquitinating enzymes

et al. 2016

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Post-translational modifications (PTMs) of stemness-related proteins are essential for stem cell maintenance and differentiation. In stem cell self-renewal and differentiation, PTM of stemness-related proteins is tightly regulated because the modified proteins execute various stem cell fate choices. Ubiquitination and deubiquitination, which regulate protein turnover of several stemness-related proteins, must be carefully coordinated to ensure optimal embryonic stem cell maintenance and differentiation. Deubiquitinating enzymes (DUBs), which specifically disassemble ubiquitin chains, are a central component in the ubiquitin-proteasome pathway. These enzymes often control the balance between ubiquitination and deubiquitination. To maintain stemness and achieve efficient differentiation, the ubiquitination and deubiquitination molecular switches must operate in a balanced manner. Here we summarize the current information on DUBs, with a focus on their regulation of stem cell fate determination and deubiquitinase inhibition as a therapeutic strategy. Furthermore, we discuss the possibility of using DUBs with defined stem cell transcription factors to enhance cellular reprogramming efficiency and cell fate conversion. Our review provides new insight into DUB activity by emphasizing their cellular role in regulating stem cell fate. This role paves the way for future research focused on specific DUBs or deubiquitinated substrates as key regulators of pluripotency and stem cell differentiation.

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Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

Section: Deubiquitinating Enzymes As Targets For Therapeuticsmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of pluripotency and differentiation by deubiquitinating enzymes

et al. 2016

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“…Based on the mechanism of enzymatic cleavage, DUBs can be divided into two main classes: cysteine proteases and zinc metalloproteases. Based on sequence and domain conservation, DUBs can also be divided into six subfamilies: ubiquitin-specific proteases (USPs), ovarian-tumor proteases (OTUs), Machado–Joseph disease protein domain proteases (MJDs), ubiquitin carboxy-terminal hydrolases (UCHs), monocyte chemotactic protein-induced protein (MCPIP) and JAMM/MPN domain-associated metallopeptidases (JAMMs) (D'Arcy et al, 2015; Pfoh et al, 2015; Kemp, 2016; Harrigan et al, 2018). Among these DUBs, USPs are the most numerous classes with ~60 proteases in humans, with sizes ranging from 50 to 300 kDa (Pfoh et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy

et al. 2018

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Dysfunction or dysregulation of the ubiquitin proteasome system (UPS) is closely related to tumorigenesis and the development of multiple cancers. Targeting the UPS provides a new anticancer therapeutic strategy, but clinically available UPS-targeted inhibitors, including lenalidomide and bortezomib, are limited to treat solid tumors. Under physiological conditions, deubiquitinases or deubiquitinating enzymes (DUBs) play vital roles in the UPS by removing ubiquitin from substrate proteins and regulating their proteasomal degradation and sub-localization, thus maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis. The aberrant expression or function of DUBs generally leads to the occurrence and progression of a series of disorders, including malignant tumors. Therefore, targeting DUBs is a novel anticancer therapeutic strategy. Ubiquitin-specific proteases (USPs) are the largest subfamily of DUBs which have attracted considerable interest as anticancer targets. Most of USPs are abnormally activated or expressed in a variety of malignant tumors or in the tumor microenvironment, making them ideal anticancer target candidates, which indicates that USPs inhibitors may be a class of potential anticancer therapeutic agents. However, there are no relevant inhibitors targeting USPs have entered clinical trial so far. In this review, we will summarize the roles and mechanisms of USPs in malignant transformation and progression as well as recent advances of small-molecule inhibitors targeting USPs.

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Discovery of a Potent and Selective Degrader for USP7

Yuan

Shi

et al. 2022

Angewandte Chemie

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The tumor suppressor p53 is the most frequently mutated gene in human cancer and more than half of cancers contain p53 mutations. The development of novel and effective therapeutic strategies for p53 mutant cancer therapy is a big challenge and highly desirable. Ubiquitin-specific protease 7 (USP7), also known as HAUSP, is a deubiquitinating enzyme and proposed to stabilize the oncogenic E3 ubiquitin ligase MDM2 that promotes the proteosomal degradation of p53. Herein, we report the design and characterization of U7D-1 as the first selective USP7-degrading Proteolysis Targeting Chimera (PROTAC). U7D-1 showed selective and effective USP7 degradation, and maintained potent cell growth inhibition in p53 mutant cancer cells, with USP7 inhibitor showing no activity. These data clearly demonstrated the practicality and importance of PROTAC as a preliminary chemical tool for investigating USP7 protein functions and a promising method for potential p53 mutant cancer therapy.

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Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors

Cited by 67 publications

References 116 publications

Regulation of pluripotency and differentiation by deubiquitinating enzymes

Regulation of pluripotency and differentiation by deubiquitinating enzymes

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy

Discovery of a Potent and Selective Degrader for USP7

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