更新于：2024-11-01

OTUB1 x USP8

更新于：2024-11-01

基本信息

关联

项与 OTUB1 x USP8 相关的药物

OTUB1/USP8 dual inhibitor 61(Chinese Academy of Sciences)

靶点

OTUB1 x USP8

作用机制

OTUB1抑制剂 [+1]

在研机构

复旦大学 [+2]

原研机构

上海交通大学 [+2]

在研适应症

非小细胞肺癌

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 OTUB1 x USP8 相关的临床结果

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100 项与 OTUB1 x USP8 相关的转化医学

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0 项与 OTUB1 x USP8 相关的专利（医药）

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项与 OTUB1 x USP8 相关的文献（医药）

2022-10-27·Journal of Medicinal Chemistry1区 · 医学

Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer

1区 · 医学

Article

作者: Shen, Jiali ; Zhang, Xiao ; Zhuang, Guanglei ; Li, Ying ; Shan, Hengyue ; Tan, Lingli ; Chen, Gang ; Tan, Li ; Han, Chao ; Lu, Kuankuan ; Zhang, Zhenfeng ; Xiang, Huaijiang ; Qi, Chunting

Deubiquitinating enzymes (DUBs) are key regulatory components of the ubiquitination system. Many DUBs have been revealed to play key roles in normal physiology and diseases. However, only very limited DUB members have well-characterized inhibitors. OTUB1 and USP8 are two DUBs reported to promote both immune evasion and tumorigenesis in tumor models, yet their targeted inhibitors are in the early stages of development. Here, we describe the lead identification and optimization of an OTUB1/USP8 dual inhibitor, 61, which exhibits highly potent and selective inhibition of both targets with subnanomolar IC₅₀s in vitro. By inhibiting both DUBs, 61 phenocopies the double knockdown of OTUB1/USP8 and exerts pronounced antiproliferative effects in H1975 and other non-small-cell lung cancer (NSCLC) cell lines. Moreover, 61 efficaciously mitigates tumor growth in vivo. Collectively, our results provide a useful tool for pharmacological perturbation of OTUB1/USP8 and introduce a promising therapeutic strategy of dual DUB inhibition for treating NSCLC.

Allergologia et Immunopathologia

Overexpression of USP8 inhibits inflammation and ferroptosis in chronic obstructive pulmonary disease by regulating the OTUB1/SLC7A11 signaling pathway

Article

作者: Zhang, Yu ; Zhu, Dan ; Zhou, Ying ; Huang, Xiufeng ; Liu, Lu ; Xu, Di ; Chen, Zhihai

Background: Chronic obstructive pulmonary disease (COPD) is a familiar disease, and owns high morbidity and mortality, which critically damages the health of patients. Ubiquitin-specific peptidase 8 (USP8) is a pivotal protein to join in the regulation of some diseases. In a previous report, it was determined that USP8 expression is down-regulated in LPS-treated BEAS-2B cells, and USP8 restrains inflammatory response and accelerates cell viability. However, the regulatory roles of USP8 on ferroptosis in COPD are rarely reported, and the associated molecular mechanisms keep vague. Objective: To investigate the regulatory functions of USP8 in COPD progression. Material and Methods: The lung functions were measured through the Buxco Fine Pointe Series Whole Body Plethysmography (WBP). The Fe level was tested through the Fe assay kit. The protein expressions were assessed through western blot. The levels of tumor necrosis -factor-α, interleukin 6, and interleukin 8 were evaluated through enzyme-linked immunosorbent serologic assay. Cell viability was tested through CCK-8 assay. Results: In this work, it was discovered that overexpression of USP8 improved lung function in COPD mice. In addition, overexpression of USP8 repressed ferroptosis by regulating glutathione peroxidase 4 and acyl-CoA synthetase long-chain family 4 expressions in COPD mice. Overexpression of USP8 suppressed inflammation in COPD mice. Furthermore, overexpression of USP8 suppressed ferroptosis in COPD cell model. At last, it was verified that overexpression of USP8 accelerated ubiquitin aldehyde-binding protein 1 (OTUB1)/solute carrier family 7 member 11 (SLC7A11) pathway. Conclusion: This study manifested that overexpression of USP8 restrained inflammation and ferroptosis in COPD by regulating the OTUB1/SLC7A11 signaling pathway. This discovery hinted that USP8 could be a potential target for COPD treatment.

Frontiers in Molecular Biosciences3区 · 生物学

OTUB1 Recruits Tumor Infiltrating Lymphocytes and Is a Prognostic Marker in Digestive Cancers

3区 · 生物学

ArticleOA

作者: Qiu, Wenlong ; Zhang, Wenhao

BACKGROUNDThe deubiquitinating enzyme (DUB) OTUB1 can regulate the process of ubiquitination, but the influence of OTUB1 on immunity, apoptosis, autophagy, and the prognosis of digestive cancers requires further exploration.METHODSOTUB1 expression was analyzed with the Oncomine and TIMER database. Kaplan-Meier plotter was used to calculate the association between OTUB1 and clinical prognosis. The regulation of OTUB1 on cancer immunocyte infiltration was determined by the TIMER database. The interaction between OTUB1 and immune genes, gene expression profiling (GEP), key genes of apoptosis and autophagy were analyzed via GEPIA. Protein-protein interaction (PPI), gene expression profiling (GEP), and functional pathway enrichment were also performed with the STRING and Pathway Common databases, respectively.RESULTSHigh OTUB1 expression was found in CHOL, LIHC, READ, ESCA, and COAD, which was significantly associated with the poorer OS of LIHC (HR = 2.07, 95% CI = 1.30-3.30, P = 0.002), with modifications by sex, stage, grade, and mutant burden. OTUB1 can promote the recruitment of B cells, CD8 + T cells, macrophages in ESCA, B cells, and neutrophils in LIHC. We determined a significant interaction between OTUB1 and USP8, RNF128, LRIG1, UBB, UBC, STAM2, RNF41, EGFR, RPS27A, and HGS by PPI. This functional pathway indicates the regulatory role of OTUB1on immune, apoptosis, and autophagy through its interaction with TP53 and ATG.CONCLUSIONSOTUB1 performed as a molecular indicator of poor prognosis in digestive cancers, regulated the infiltration of tumor immunocytes, and exerted a significant influence on apoptosis and autophagy. OTUB1 is a potential antitumor target for digestive tumors.