更新于：2024-09-19

UBASH3B

更新于：2024-09-19

基本信息

别名

Cbl-interacting protein p70、KIAA1959、STS-1

+ [9]

简介

Interferes with CBL-mediated down-regulation and degradation of receptor-type tyrosine kinases. Promotes accumulation of activated target receptors, such as T-cell receptors and EGFR, on the cell surface. Exhibits tyrosine phosphatase activity toward several substrates including EGFR, FAK, SYK, and ZAP70. Down-regulates proteins that are dually modified by both protein tyrosine phosphorylation and ubiquitination.

关联

项与 UBASH3B 相关的药物

Rebamipide

雷巴米特

靶点

UBASH3B

作用机制

UBASH3B inhibitors

在研机构

Hokkaido University [+3]

原研机构

Otsuka Pharmaceutical Co., Ltd.

在研适应症

胃炎 [+2]

非在研适应症

急性胃炎 [+11]

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期1990-09-28

142

项与 UBASH3B 相关的临床试验

CTR20240809 / CompletedN/A

健康受试者单次口服瑞巴派特片的随机、开放、两周期、两序列、双交叉，空腹和高脂餐后给药条件下的人体生物等效性试验。

主要目的：以药代动力学参数为终点指标，比较空腹和高脂餐后给药条件下，安徽金太阳生化药业有限公司生产的瑞巴派特片与OTSUKA PHARMACEUTICAL Co.,Ltd.（大塚制薬株式会社）原研的瑞巴派特片在健康成年人群中吸收程度和速度的差异，对两制剂的生物等效性进行评价。次要目的：评价空腹和高脂餐后给药条件下，安徽金太阳生化药业有限公司生产的瑞巴派特片在健康成年人群中的安全性。

开始日期2024-03-13

申办/合作机构

安徽金太阳生化药业有限公司

CTR20240111 / CompletedN/A

浙江大冢制药有限公司生产的瑞巴派特片（商品名：膜固思达®）与原研药瑞巴派特片（商品名：Mucosta®）在中国健康受试者空腹和餐后状态下的单中心、随机、开放、两制剂、两周期、两序列、单次给药、双交叉生物等效性研究

（1）主要目的：以瑞巴派特的主要药代动力学参数（AUC和Cmax）为生物等效性的评价指标，在中国健康受试者空腹和餐后状态下评估受试制剂（浙江大冢制药有限公司生产的瑞巴派特片，规格：0.1g；商品名：膜固思达®）和参比制剂（OTSUKA PHARMACEUTICAL Co.,Ltd.持证的瑞巴派特片，规格：0.1g；商品名：Mucosta®）的生物等效性。（2）次要目的：观察空腹和餐后状态下受试制剂和参比制剂的安全性。

开始日期2024-01-22

申办/合作机构

大冢制药研发（北京）有限公司

ChiCTR2300078984 / Recruiting临床4期IIT

Randomized, controlled, multicenter clinical study of rebamipide in the prevention of gout attack

开始日期2024-01-01

申办/合作机构

安徽医科大学第一附属医院

100 项与 UBASH3B 相关的临床结果

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100 项与 UBASH3B 相关的转化医学

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0 项与 UBASH3B 相关的专利（医药）

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124

项与 UBASH3B 相关的文献（医药）

2024-03-12·Clinical and Experimental Immunology

Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease

Article

作者: Berentsen, Sigbjørn ; Munthe, Ludvig A ; Tierens, Anne ; Trøen, Gunhild ; Østlie, Ingunn ; Małecki, Jędrzej ; Delabie, Jan ; Tjønnfjord, Geir E ; Małecka, Agnieszka

AbstractCold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.

2024-02-08·Journal of Medicinal Chemistry1区 · 医学

Rebamipide and Derivatives are Potent, Selective Inhibitors of Histidine Phosphatase Activity of the Suppressor of T Cell Receptor Signaling Proteins

1区 · 医学

Article

作者: Jordan, Luis Ortiz ; Scampavia, Louis ; French, Jarrod B ; Dey, Raja ; Reddy, Kanamata ; Smith, Emery ; Aziz, Faisal ; Shumate, Justin ; Hicks, Katherine A ; Spicer, Timothy P ; Fernandez Vega, Virneliz ; Carpino, Nicholas ; Rao, Sumitha

The suppressor of T cell receptor signaling (Sts) proteins are negative regulators of immune signaling. Genetic inactivation of these proteins leads to significant resistance to infection. From a 590,000 compound high-throughput screen, we identified the 2-(1H)-quinolinone derivative, rebamipide, as a putative inhibitor of Sts phosphatase activity. Rebamipide, and a small library of derivatives, are competitive, selective inhibitors of Sts-1 with IC₅₀ values from low to submicromolar. SAR analysis indicates that the quinolinone, the acid, and the amide moieties are all essential for activity. A crystal structure confirmed the SAR and reveals key interactions between this class of compound and the protein. Although rebamipide has poor cell permeability, we demonstrated that a liposomal preparation can inactivate the phosphatase activity of Sts-1 in cells. These studies demonstrate that Sts-1 enzyme activity can be pharmacologically inactivated and provide foundational tools and insights for the development of immune-enhancing therapies that target the Sts proteins.

2023-12-01·Immunity

TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments

Article

作者: Wang, Zhi-En ; Tsai, Yuan-Li ; Barber, Diane ; Shah, Neel H ; Lwin, Yee May ; Arias-Badia, Marcel ; Fong, Lawrence ; Kuriyan, John ; Kadlecek, Theresa A ; Weiss, Arthur ; Srinath, Aahir

T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity.