Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

Chen, Shiyao; Liu, Yunqi; Zhou, Huchen

doi:10.3390/ijms22094546

Cited by 76 publications

(59 citation statements)

References 166 publications

(162 reference statements)

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“…Studies carried out in the past few decades have revealed the critical roles of DUBs in various diseases, especially cancer, providing sufficient evidence for the development of these molecules as potential pharmaceutical targets, and considerable progress has been made in the development of inhibitors against several DUBs such as USP1 and USP7 ( Harrigan et al, 2018 ; Chen S. et al, 2021 ; Nininahazwe et al, 2021 ). Nevertheless, progress in the development of USP21 inhibitors remains limited.…”

Section: Inhibitors Of Usp21mentioning

confidence: 99%

Insights Into the Properties, Biological Functions, and Regulation of USP21

et al. 2022

Front. Pharmacol.

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Deubiquitylating enzymes (DUBs) antagonize ubiquitination by removing ubiquitin from their substrates. The role of DUBs in controlling various physiological and pathological processes has been extensively studied, and some members of DUBs have been identified as potential therapeutic targets in diseases ranging from tumors to neurodegeneration. Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Although USP21 was discovered late and early research progress was slow, numerous studies in the last decade have gradually revealed the importance of USP21 in a wide variety of biological processes. In particular, the pro-carcinogenic effect of USP21 has been well elucidated in the last 2 years. In the present review, we provide a comprehensive overview of the current knowledge on USP21, including its properties, biological functions, pathophysiological roles, and cellular regulation. Limited pharmacological interventions for USP21 have also been introduced, highlighting the importance of developing novel and specific inhibitors targeting USP21.

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Section: Inhibitors Of Usp21mentioning

confidence: 99%

Insights Into the Properties, Biological Functions, and Regulation of USP21

et al. 2022

Front. Pharmacol.

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“…Studies have shown that USPs (USP2a, USP4, USP9X, USP15, and USP26) are involved in the regulation of TGF-β signaling pathways in various cancers ( 17 ). For example, USP9X can control the monoubiquitination of SMAD4 to regulate TGF-β-mediated cancer metastasis ( 101 ).…”

Section: Important Signaling Pathways In Pc Tmementioning

confidence: 99%

“…The K48 and K63 chains are the most studied ubiquitin chain linkages that guide the expression of substrate proteins. The K48 ubiquitin chain has been shown to play an important role in ATP-dependent proteasomal degradation ( 16 ), while the K63 ubiquitin chain is mainly involved in the modification of protein location and function ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Role of ubiquitin specific proteases in the immune microenvironment of prostate cancer: A new direction

et al. 2022

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Regulation of ubiquitination is associated with multiple processes of tumorigenesis and development, including regulation of the tumor immune microenvironment. Deubiquitinating enzymes (DUBs) can remove ubiquitin chains from substrates, thereby stabilizing target proteins and altering and remodeling biological processes. During tumorigenesis, deubiquitination-altered biological processes are closely related to tumor metabolism, stemness, and the immune microenvironment. Recently, tumor microenvironment (TME) modulation strategies have attracted considerable attention in cancer immunotherapy. Targeting immunosuppressive mechanisms in the TME has revolutionized cancer therapy. Prostate cancer (PC) is one of the most common cancers and the second most common cause of cancer-related death in men worldwide. While immune checkpoint inhibition has produced meaningful therapeutic effects in many cancer types, clinical trials of anti-CTLA4 or anti-PD1 have not shown a clear advantage in PC patients. TME affects PC progression and also enables tumor cell immune evasion by activating the PD-1/PD-L1 axis. Over the past few decades, an increasing number of studies have demonstrated that deubiquitination in PC immune microenvironment may modulate the host immune system’s response to the tumor. As the largest and most diverse group of DUBs, ubiquitin-specific proteases (USPs) play an important role in regulating T cell development and function. According to current studies, USPs exhibit a high expression signature in PC and may promote tumorigenesis. Elevated expression of USPs often indicates poor tumor prognosis, suggesting that USPs are expected to develop as the markers of tumor prognosis and even potential drug targets for anti-tumor therapy. Herein, we first summarized recent advances of USPs in PC and focused on the relationship between USPs and immunity. Additionally, we clarified the resistance mechanisms of USPs to targeted drugs in PC. Finally, we reviewed the major achievement of targeting USPs in cancers.

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“…funding acquisition: X.W. All authors have read and agreed to the published version of the manuscript [128,138] Author Contributions: Conceptualization, X.W. and H.Z.…”

Section: Conflicts Of Interestmentioning

confidence: 99%

Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery

Zhang

Wei

2021

Life

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Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug targets. DUBs have shown significant roles in regulating breast cancer growth, metastasis, resistance to current therapies, and several canonical oncogenic signaling pathways. In addition, specific DUB inhibitors have been identified and are expected to benefit breast cancer patients in the future. Here, we review current knowledge about the effects and molecular mechanisms of DUBs in breast cancer, providing novel insight into treatments of breast cancer-targeting DUBs.

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Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

Cited by 76 publications

References 166 publications

Insights Into the Properties, Biological Functions, and Regulation of USP21

Insights Into the Properties, Biological Functions, and Regulation of USP21

Role of ubiquitin specific proteases in the immune microenvironment of prostate cancer: A new direction

Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery

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