更新于：2024-11-01

TOB2

更新于：2024-11-01

基本信息

别名

APRO5、bK223H9、KIAA1663

+ [8]

简介

Anti-proliferative protein inhibits cell cycle progression from the G0/G1 to S phases.

关联

项与 TOB2 相关的药物

S115

靶点

TOB2 x ubiquitin

作用机制

TOB2 agonists [+2]

在研机构

上海交通大学

原研机构

上海交通大学

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TOB2 相关的临床结果

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100 项与 TOB2 相关的转化医学

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0 项与 TOB2 相关的专利（医药）

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188

项与 TOB2 相关的文献（医药）

2024-09-01·Microvascular Research

Circulating miRNA-4701-3p as a predictive biomarker of cardiovascular disease which induces angiogenesis by inhibition of TOB2

Article

作者: Kim, Young-Hak ; Ha, Chang Hoon ; Jeong, I Jin-Yong ; Yoon, Bo Hyun ; Lee, Seung Min ; Pack, Chan-Gi ; Kim, Inki ; Lee, Jin Woo

Angiogenesis is mainly regulated by the delivery of VEGF-dependent signaling to cells. However, the angiogenesis mechanism regulated by VEGF-induced miRNA is still not understood. After VEGF treatment in HUVECs, we screened the changed miRNAs through small-RNA sequencing and found VEGF-induced miR-4701-3p. Furthermore, the GFP reporter gene was used to reveal that TOB2 expression was regulated by miR-4701-3p, and it was found that TOB2 and miR-4701-3p modulation could cause angiogenesis in an in-vitro angiogenic assay. Through the luciferase assay, it was confirmed that the activation of the angiogenic transcription factor MEF2 was regulated by the suppression and overexpression of TOB2 and miR-4701-3p. As a result, MEF2 downstream gene mRNAs that induce angiogenic function were regulated. We used the NCBI GEO datasets to reveal that the expression of TOB2 and MEF2 was significantly changed in cardiovascular disease. Finally, it was confirmed that the expression of circulating miR-4701-3p in the blood of myocardial infarction patients was remarkably increased. In patients with myocardial infarction, circulating miR-4701-3p was increased regardless of age, BMI, and sex, and showed high AUC levels in specificity and sensitivity analysis (AUROC) (AUC = 0.8451, 95 % CI 0.78-0.90). Our data showed TOB2-mediated modulation of MEF2 and its angiogenesis by VEGF-induced miR-4701-3p in vascular endothelial cells. In addition, through bioinformatics analysis using GEO data, changes in TOB2 and MEF2 were revealed in cardiovascular disease. We suggest that circulating miR-4701-3p has high potential as a biomarker for myocardial infarction.

2024-05-01·Chemosphere

Multilevel assessment of carbamazepine effects: An integrative approach using zebrafish early-life stages

Article

作者: Camargo, Níchollas Serafim ; Andrade, Thayres Sousa ; Pic-Taylor, Aline ; Grisolia, Cesar Koppe ; Silva, Muriel Lopes da ; Sousa-Moura, Diego ; Domingues, Inês ; Oliveira, Rhaul de ; Lisboa, Carolina Almeida ; Villacis, Rolando André Rios

Carbamazepine (CBZ) is the most commonly used drug in epilepsy treatment, and its metabolites are commonly detected among persistent pharmaceuticals in the aquatic environment. This study aimed to investigate CBZ effects on early-life-stage zebrafish (Danio rerio) (from 2 to 168 hpf) by employing of an integrative approach linking endpoints from molecular to individual level: (i) development; (ii) locomotor activity; (iii) biochemical markers (lactate dehydrogenase, glutathione-S-transferase, acetylcholinesterase and catalase) and (iv) transcriptome analysis using microarray. A 168 h - LC₅₀ of 73.4 mg L^-1 and a 72 h - EC₅₀ of 66.8 mg L^-1 for hatching were calculated while developmental effects (oedemas and tail deformities) were observed at CBZ concentrations above 37.3 mg L^-1. At the biochemical level, AChE activity proved to be the most sensitive parameter, as evidenced by its decrease across all concentrations tested (∼25% maximum reduction, LOEC (lowest observed effect concentration) < 0.6 μg L^-1). Locomotor behaviour seemed to be depressed by CBZ although this effect was only evident at the highest concentration tested (50 mg L^-1). Molecular analysis revealed a dose-dependent effect of CBZ on gene expression. Although only 25 genes were deregulated in organisms exposed to CBZ when compared to controls, both 0.6 and 2812 μg L^-1 treatments impaired gene expression related to development (e.g. crygmxl1, org, klf2a, otos, stx16 and tob2) and the nervous system (e.g. Rtn3, Gdf10, Rtn3), while activated genes were associated with behavioural response (e.g. prlbr and taar). Altogether, our results indicate that environmentally relevant CBZ concentrations might affect biochemical and genetic traits of fish. Thus, the environmental risk of CBZ cannot be neglected, especially in a realistic scenario of constant input of domestic effluents into aquatic systems.

2024-03-01·International Journal of Biological Macromolecules

Hsa_circ_0086414/transducer of ERBB2 (TOB2) axis-driven lipid elimination and tumor suppression in clear cell renal cell cancer via perilipin 3

Article

作者: Yuan, Hongwei ; Lu, Feiyi ; Xiao, Wen ; Yu, Tiexi ; Wang, Cheng ; Dong, Wei ; Li, Weiquan ; Meng, Xiangui ; Zhang, Xiaoping ; Yang, Wei

BACKGROUNDRenal cell cancer (RCC) is characterized by abnormal lipid accumulation. However, the specific mechanism by which such lipid deposition is eliminated remains unclear. Circular RNAs (circRNAs) widely regulate various biological processes, but the effect of circRNAs on lipid metabolism in cancers, especially clear cell renal cell carcinoma (ccRCC), remains poorly understood.METHODSThe downregulated circRNA, hsa_circ_0086414, was identified from high-throughput RNA-sequencing data of human ccRCC and pair-matched normal tissues. The target relationship between circRNA_0086414 and miR-661, and the transducer of ERBB2 (TOB2) was predicted using publicly available software programs and verified by luciferase reporter assays. The clinical prognostic value of TOB2 was evaluated by bioinformatic analysis. The expression levels of circRNA_0086414, miR-661, TOB2, and perilipin 3 (PLIN3) were measured by quantitative reverse-transcription polymerase chain reaction or western blot analysis. Cell Counting Kit-8, transwell assays, and xenograft models were employed to assess the biological behaviors of the hsa_circ_0086414/TOB2 axis. Oil Red staining and triglyceride assay was conducted to assess lipid deposition.RESULTSHerein, we identified a downregulated circRNA, hsa_circ_0086414. Functionally, the restored hsa_circ_0086414 inhibited ccRCC proliferation, metastasis, and lipid accumulation in vitro and in vivo. Furthermore, the downregulated TOB2 predicted adverse prognosis and promoted cancer progression and lipid deposition in ccRCC. Mechanically, the binding of hsa_circ_0086414 to miR-661, as a miRNA sponge, upregulates the expression of TOB2, wielding an anti-oncogene effect. Importantly, the restored hsa_circ_0086414/TOB2 axis significantly contributed to the elimination of lipid deposition by inhibiting the lipid metabolism regulator PLIN3 in ccRCC cells.CONCLUSIONSOur data highlight the importance of the hsa_circ_0086414/TOB2/PLIN3 axis as a tumor suppressor and lipid eliminator in ccRCC. The positive modulation of the hsa_circ_0086414/TOB2 axis might lead to the development of novel treatment strategies for ccRCC.

项与 TOB2 相关的新闻（医药）

2024-06-12

·药研网

KRAS与EGFR联合，双靶向治疗优势明显

在近期的2024 ASCO年会上，劲方医药以口头报告形式公布了KRASG12C抑制剂fulzerasib（GFH925）联合西妥昔单抗一线治疗非小细胞肺癌的II期临床研究数据。此项具有开创性的一线疗法数据显示了鼓舞人心的疗效、和优于二线及以上单药疗法的安全性/耐受性，也是全球首个KRAS G12C抑制剂联合EGFR抑制剂用于一线NSCLC治疗的临床数据在国际学术会议公布。 KROCUS研究数据表皮生长因子受体（Epidermal Growth Factor Receptor，简称EGFR）和Kirsten大鼠肉瘤2型病毒癌基因同源物（Kirsten Rat Sarcoma Viral Oncogene Homolog，简称KRAS）在细胞生长和分裂过程中扮演着关键角色。然而，当这些基因发生突变时，往往会引发一系列严重的疾病，尤其是各类癌症。 EGFR EGFR是一种跨膜蛋白，属于受体酪氨酸激酶，主要作用是通过与表皮生长因子结合，激活下游信号通路，参与细胞生长和增殖的调控。EGFR也是ErbB家族的成员，该家族包括EGFR(ErbB-1)和另外三个成员，HER2(ErbB-2)、HER3(ErbB-3)和HER4(ErbB-4)。一系列研究表明，EGFR的过量表达或其基因突变与多种癌症的发生密切相关。当EGFR发生突变时，导致EGFR信号通路在没有配体结合的情况持续激活，从而导致细胞异常增殖。最为典型的是非小细胞肺癌（Non-Small Cell Lung Cancer，简称NSCLC）。在NSCLC患者中，约有10%-15%的患者存在EGFR突变。这种突变导致EGFR持续活化，进而推动癌细胞的异常快速生长与扩散。此外，乳腺癌、结肠癌、胶质母细胞瘤等也与EGFR的异常活性有关。 KRAS 相比之下，KRAS作为另一个关键信号分子，其突变同样在多种癌症中扮演了重要角色。KRAS属于小GTP酶家族，属于RAS基因家族中的一员，主要负责传递细胞外信号至细胞核，调控细胞周期和凋亡。 KRAS突变会导致其构象改变，使其处于持续活化状态。这种异常活性能促使细胞失去正常调控，进而演变为恶性肿瘤。在结直肠癌、胰腺癌及肺癌等疾病中，KRAS突变的发生率较高。RAS基因驱动的癌症中有86%是由KRAS的突变引起的，90%的胰腺癌、30~40%的结肠癌、15~20%的肺癌中都存在KRAS基因突变。由于KRAS蛋白体积小，表面光滑，几乎没有适合小分子结合的口袋，同时KRAS对GTP亲和力极强，药物很难与GTP竞争，在过去40年的研究中，一直被认为是一个具有挑战性的治疗靶点，可谓“不可成药靶点”。近几年，KRAS靶向药物有了惊人的进展，在KRAS(G12C)抑制剂方面，AMG510(Sotorasib)和MRTX849(Adagrasib)，目前已获批上市。吉满生物根据市场需求和研究现状，推出Kinase BaF3细胞系，可用于评估小分子药物对激酶的靶向抑制作用, 助力药物研发。详情咨询吉满客服，联系18916119826(同微信）！ KRAS与EGFR联合疗法新突破 KRAS G12C抑制剂与抗 EGFR 药物联合使用，表现出有意义的临床活性。 Divarasib（GDC-6036） Divarasib（GDC-6036）是一种相较于 Sotorasib 和 Adagrasib 而言，具有高效力（高达 5-20 倍）和高选择性（高达 50 倍）的 KRAS G12C 抑制剂，能够不可逆转地将蛋白锁定为非活性状态，进而关闭致癌信号传导。尽管单药 Divarasib 在 CRC 患者中具有不俗的抗肿瘤活性，但耐药依然是这部分患者需要面临的关键问题。去年12月，Nature medicine 发布了 Divarasib+西妥昔单抗用于KRAS G12C突变转移性结直肠癌1b期临床研究结果，其出色的疗效为未来KRAS G12C结直肠癌治疗带来曙光。研究证实了 Divarasib 联合西妥昔单抗较单药 Divarasib 抗肿瘤活性有所提高，这与 RAS-MAPK 通路在 KRAS G12C 抑制后导致的 EGFR 介导的调节性反馈调节假说相一致。在先前未接受 KRAS G12C 抑制剂的转移性 CRC 患者中，Divarasib 单药 ORR 为 35.9%，而本研究发现联合治疗的ORR提升至 62.5%，且高于既往研究中其他 KRAS G12C 抑制剂 960 mg sotorasib +帕尼单抗的ORR (26.4%) 和 adagrasib + 西妥昔单抗 ORR (46%)，且在本次研究的中位 PFS（8.1 个月）是所有 KRAS G12C 抑制剂治疗转移性 CRC 临床研究中最长的PFS。虽然研究中所有患者均出现了 TRAE，但绝大多数（91.6%）为 1-2 级，总体上 Divarasib 联合西妥昔单抗的耐受性良好，安全性可控。 Fulzerasib 在2024ASCO年会上，劲方医药以口头报告形式公布了KRAS G12C抑制剂fulzerasib联合西妥昔单抗一线治疗非小细胞肺癌的II期临床研究数据。 Fulzerasib于2023年3月进入Ib/II期欧洲多中心试验。截至2024年4月19日，共有40例未经治疗的KRAS G12C突变非小细胞患者纳入fulzerasib、西妥昔单抗的联合疗法单臂临床试验，其中33例接受过至少一次治疗后肿瘤评估：ORR为81.8%、DCR为100%；多数可评估患者（27/33）达到肿瘤缓解，其中1例达到完全缓解，另外2例达到部分缓解的患者也观察到靶病灶缩小100%。且表现出良好可控的安全性/耐受性，不良事件（TRAE）发生率、三级以上TRAE事件均小于fulzerasib单药治疗二线及以上NSCLC临床试验。目前全球有多个KRAS G12C抑制剂、EGFR抑制剂联用瞄准后线CRC，劲方则尝试将双靶点协同机制的临床验证从后线CRC推向一线 NSCLC。总之，EGFR和KRAS基因突变引发的疾病，尤其是癌症，为医学领域带来了重大挑战。但随着医学进步，我们在理解及治疗这些疾病方面也取得了显著进展。未来，随着更多靶向治疗方法的开发与应用，相信可以为更多患者带来福音。吉满生物吉满生物助力药物研发，自主研发了一系列Kinase Ba/F3细胞系。Ba/F3细胞是一种IL-3依赖的的前体B细胞，而一些蛋白激酶可以代替IL-3使Ba/F3细胞依赖性生长。在 Ba/F3（小鼠原B细胞）上进行改造，引入相应表达激酶基因，这些基因能作为Ba/F3的驱动基因，让Ba/F3不再依赖IL-3而增殖，进而激酶基因成为Ba/F3增殖依赖的驱动基因，用于评估小分子药物对激酶的靶向抑制作用。产品列表产品优势基因变化背景单一可控，细胞生存依赖唯一转基因导入的活化激酶，不存在脱靶现象，能够更加准确快速地表明药物的作用机制。结合高通量药物筛选平台，实现了批量化合物精准靶点检测与选择性评价，检测药物的靶点选择性，评价药物毒副反应。数据展示 GM-C29680 H_EGFR(L858R-T790M-C797S) BAF3 Cell Line使用Osimertinib ；Erlotinib (OSI-774；Afatinib ；EGFR-IN-7(TQB3804）杀伤验证结果 H_EGFR(L858R-T790M-C797S) BAF3 Cell Line使用EGF Receptor (C74B9) Rabbit mAb 抗体WB验证结果 H_EGFR(L858R-T790M-C797S) BAF3 Cell Line突变位点Sanger测序结果 GM-C29505 H_KRAS(G12C-R68S) BaF3 Cell Line使用MRTX1133；MRTX849；AMG510杀伤验证结果 H_KRAS(G12C-R68S) BaF3 Cell Line突变位点Sanger测序结果联系我们吉满生物助力药物研发，紧随前沿靶点资讯，储备几百株现货细胞，覆盖GPCR、细胞因子、免疫检查点、TAA等多领域，截止当前已布局近300个热门靶向药靶点，1000余株细胞系，旨在助力、加速大分子早期研发，做到进口细胞的国产替代。同时可根据客户需求提供细胞系服务。扫码咨询扫码找现货

ASCO会议临床结果