更新于：2024-11-01

HSP90B

更新于：2024-11-01

基本信息

别名

Heat shock 84 kDa、heat shock 90kD protein 1, beta、heat shock 90kDa protein 1, beta

+ [10]

简介

Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:16478993, PubMed:19696785). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:27295069, PubMed:26991466). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels. They first alter the steady-state levels of certain transcription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Promotes cell differentiation by chaperoning BIRC2 and thereby protecting from auto-ubiquitination and degradation by the proteasomal machinery (PubMed:18239673). Main chaperone involved in the phosphorylation/activation of the STAT1 by chaperoning both JAK2 and PRKCE under heat shock and in turn, activates its own transcription (PubMed:20353823). Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1; the translocation process is mediated by the cargo receptor TMED10 (PubMed:32272059). (Microbial infection) Binding to N.meningitidis NadA stimulates monocytes (PubMed:21949862). Seems to interfere with N.meningitidis NadA-mediated invasion of human cells (Probable).

关联

项与 HSP90B 相关的药物

Pimitespib

靶点

HSP90A x HSP90B

作用机制

HSP90A抑制剂 [+1]

在研机构

大鹏药品信息咨询（北京）有限公司 [+2]

原研机构

Taiho Pharmaceutical Co., Ltd.

在研适应症

胃肠道间质瘤

非在研适应症

晚期恶性实体瘤

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2022-06-20

Cemdomespib

靶点

HSP90B

作用机制

HSP90B抑制剂

在研机构

Reata Pharmaceuticals, Inc.

原研机构

Reata Pharmaceuticals, Inc.

在研适应症

糖尿病周围神经性疼痛

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

XL-888

靶点

HSP90B

作用机制

HSP90B抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 HSP90B 相关的临床试验

NCT05655598 / Withdrawn临床1期IIT

Phase Ib IIT of Heat Shock Protein 90 Inhibitor TAS-116 Combined with Cyclin-dependent Kinase 4/6 Inhibitor Palbociclib in Advanced Breast Cancer Progressing on Palbociclib & Treatment-refractory Solid Tumors with Retinoblastoma Deficiency

The purpose of this study is to evaluate the safety and efficacy of TAS-116 with palbociclib in two groups of patients:
* Patients with advanced breast cancer that has become worse after taking palbociclib alone
* Patients with cancers that have an abnormality in a gene called the "retinoblastoma gene".

开始日期2023-09-12

申办/合作机构

Brown University

CTR20232143 / Recruiting临床1期

一项TAS-116(pimitespib)联合伊马替尼治疗晚期胃肠道间质瘤患者的Ⅰ期研究

这是一项I期、开放性、多国、多中心研究。在中国患者剂量递增部分，将在中国患者中评估pimitespib单药治疗以及与伊马替尼联合治疗的安全性和耐受性。

开始日期2023-09-04

申办/合作机构

Bushu Pharmaceuticals Ltd.

[+2]

JPRN-jRCT2031230263 / Recruiting临床2期

Phase 2 platform study evaluating combination therapy with TAS-116 (pimitespib) in patients with malignant tumors - CHAPTER-Platform-201

开始日期2023-08-25

申办/合作机构

Sato Atsushi

100 项与 HSP90B 相关的临床结果

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100 项与 HSP90B 相关的转化医学

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0 项与 HSP90B 相关的专利（医药）

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1,125

项与 HSP90B 相关的文献（医药）

2025-01-01·Annals of Anatomy - Anatomischer Anzeiger

Unveiling proteomic targets in the hypothalamus of ovariectomized and estradiol-treated rats: Insights into menopausal syndrome mechanisms

Article

作者: Qin, Lihua ; Wang, Ke ; Wang, Wenjuan ; Wang, Hanfei ; Luan, Liju ; Liang, Lining ; Li, Yao ; Bai, Wenpei ; Wang, Xiangqiu ; Sun, Yanrong

BACKGROUNDMenopausal syndrome profoundly affects the physical and mental health of many women, drawing increasing attention from the medical community. However, its pathogenesis remains unclear. These symptoms are primarily driven by hormonal fluctuation. The hypothalamus, a key regulator of hormonal balance, potentially playing a critical role in the manifestation of menopausal syndrome.METHODSWe simulated the low-estrogen menopausal state using ovariectomized rats, confirmed the success of ovariectomy via histological analysis of the uterus and vagina, followed by estrogen treatment. TMT-labeled quantitative proteomics, RTqPCR, targeted proteomics and Western blotting were used to identify differentially expressed proteins and their functions in the hypothalamus under low-estrogen conditions.RESULTSOne-way ANOVA (p < 0.05) identified 295 differentially expressed proteins across the sham, ovariectomized and estrogen-treated groups. Post-ovariectomy, 103 differentially expressed proteins were upregulated and 93 were downregulated. Among these, 50 proteins were involved in hormones and neurotransmitters, immunity, metabolism and cardiovascular function. Notably, four proteins-Prkcg, Hsp90ab1, Ywhae, and Gad2-were identified as crucial regulators.CONCLUSIONSThis study elucidates the central molecular mechanism of menopausal syndrome through bioinformatics analysis of differentially expressed proteins in the hypothalamus under low-estrogen conditions, providing novel targets for the treatment of related symptoms.

2024-12-01·Current Pharmaceutical Design

Integrating Network Pharmacology, Bioinformatics, and Mendelian Randomization Analysis to Identify Hub Targets and Mechanisms of Kunkui Baoshen Decoction in Treating Diabetic Kidney Disease

Article

作者: Yu, Jiangyi ; Song, Siyuan

Objective:To uncover the potential hub targets of Kunkui Baoshen Decoction (KKBS) in alleviating Diabetic Kidney Disease (DKD).Methods:Targets associated with KKBS and DKD were curated from TCMSP, GeneCards, OMIM, and Dis- GeNET databases. Common targets were identified through intersection analysis using a Venn diagram. Employing the "Drug-component-target" approach and constructing a Protein-protein Interaction (PPI) network, pivotal components and hub targets involved in KKBS's therapeutic action against DKD were identified. Functional enrichment and Gene Set Enrichment Analysis (GSEA) elucidated the potential mechanisms of these hub targets. Molecular docking simulations validated binding interactions. Subsequently, hub targets were validated using independent cohorts and clinical datasets. Immune cell infiltration in DKD samples was assessed using ESTIMATE, CIBERSORT, and IPS algorithms. A nomogram was developed to predict DKD prevalence. Finally, causal relationships between hub targets and DKD were explored through Mendelian randomization (MR) analysis at the genetic level.Results:Jaranol, isorhamnetin, nobiletin, calycosin, and quercetin emerged as principal effective components in KKBS, with predicted modulation of the PI3K/Akt, MAPK, HIF-1, NF-kB, and IL-17 signaling pathways. The hub targets in the PPI network include proteins involved in regulating podocyte autophagy and apoptosis, managing antioxidant stress, contributing to insulin resistance, and participating in extracellular matrix deposition in DKD. Molecular docking affirmed favorable binding interactions between principal components and hub targets. Validation efforts across cohorts and databases underscored the potential of hub targets as DKD biomarkers. Among 20 model algorithms, the Extra Tree model yielded the largest Area Under the Curve (AUC) in receiver operating characteristic (ROC) analysis. MR analysis elucidated that the targets related to antioxidant stress had a positive impact on DKD, while the target associated with renal tubular basement membrane degradation had a negative impact.Conclusion:Integration of Network Pharmacology, Bioinformatics, and MR analysis unveiled the capacity of KKBS to modulate pivotal targets in the treatment of DKD.

2024-12-01·International Immunopharmacology

Bioinformatics data combined with single-cell analysis reveals patterns of immunoinflammatory infiltration and cell death in melanoma

Article

作者: Cui, Fan ; Liu, Yangying ; Rang, Zhen ; Yang, Ge ; Jin, Li

BACKGRUONDMelanoma is a common cancer in dermatology, but its molecular mechanisms remain poorly explained.AIMUtilizing single-cell analytics and bioinformatics, the work sought to discover the immunological infiltration and cellular molecular mechanisms of melanoma.METHODSMelanoma genes databases were downloaded from GeneCards, and gene expression profiles were chosen from the Gene Expression Omnibus (GSE244889). Establishing and analyzing protein-protein interaction networks for functional enrichment made use of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. The process assesses the immunological cell infiltration variations between normal and malignant samples by Immune Cell AI software program. Different cell type differences were clarified by cell quality control, filtration, removal of batch effects and cell clustering analysis using single cell analysis techniques.RESULTSUsing a variety of machine learning techniques, 20 differentially expressed hub genes were found; among these, TP53, HSP90AB1, HSPA4, RHOA, CCND1, CYCS, PPARG, NFKBIA, CAV1, ANXA5, ENO1, ITGAM, YWHAZ, RELA, SOD1, and VDAC1 were found to be significantly significant. The results of enrichment analysis demonstrated that immune response and inflammatory response were strongly associated with melanoma. Animal mitophagy, ferroptosis, the PI3K-Akt signaling pathway, and the HIF-1 signaling pathway were the primary signaling pathways implicated. Cells of immunity, T-cells, lymphocytes, B-cells, NK-cells, monocytes, and macrophages were shown to be significantly infiltrated in melanoma patients, according to analysis. Single cell analysis also demonstrated that ferroptosis is a significant mechanism of cell death that contributes to the advancement of melanoma and that macrophages are important in the disease.CONCLUSIONIn summary, different immune cell infiltrations-particularly macrophages-have a significant impact on the onset and course of melanoma, and our findings may help direct future investigations into melanoma macrophages.

项与 HSP90B 相关的新闻（医药）

2023-03-13

·生物谷

《自然·衰老》：全海马单细胞转录组学研究，全面揭示APOE4促进阿尔茨海默病发生机制

阿尔茨海默病（AD）是一种多见于老年人的神经系统退行性疾病。正如影视作品中所描述的这样，随着疾病的进展，患者逐渐忘记周围的人，忘记自己引以为傲的过去，失去丰沛的感情，最终丧失生活能力。阿尔茨海默病（AD）是一种多见于老年人的神经系统退行性疾病。正如影视作品中所描述的这样，随着疾病的进展，患者逐渐忘记周围的人，忘记自己引以为傲的过去，失去丰沛的感情，最终丧失生活能力。而有这样一类人群：APOE4基因的携带者，他们患AD的风险更高，发病也更早 [1]。长期以来，人们对APOE4基因做了大量研究，尝试揭开APOE4推动AD发生发展的秘密。但既往研究大都局限于某一种细胞或者某一条通路，让我们无法对APOE4与AD病理进程的关系建立完整的概念。近期，来自美国加利福尼亚大学的黄亚东教授团队的一项研究，通过记录小鼠大脑内单细胞核转录组学变化，发现敲除神经元内APOE4基因可改善Tau蛋白介导的胶质细胞激活，神经系统脱髓鞘改变和神经元死亡等一系列病理损伤[2]。研究成果发表在《自然•衰老》上。文章首页截图 APOE有三种等位基因，其中APOE4可以大大提高患AD的风险，而APOE2正相反，可以降低AD的发病风险。APOE3被称为野生型，对AD风险增加或减少无明显作用[3]。为了研究APOE4的作用，研究者们将表达loxP序列的人APOE3和APOE4基因的小鼠，与神经元特异性启动子Syn1-Cre小鼠杂交，得到了可以在神经元内特异性敲除APOE基因的小鼠。在此基础上，研究者们将上述模型鼠与Tau蛋白病理模型鼠PS19杂交，得到了四种转基因小鼠模型：PS19-fE3，PS19-fE3/Syn1-Cre，PS19-fE4，PS19-fE4/Syn1-Cre。这样就可以在神经元内存在或不存在APOE基因的情况下观察Tau蛋白病理变化。接下来，研究者们在小鼠10月龄时对海马中Tau蛋白病理进行了检测，实验结果表明，表达APOE4的小鼠海马区域有大量的磷酸化Tau蛋白和神经元纤维缠结。在神经元内特异性敲除APOE4后，磷酸化Tau蛋白的水平下降了81%，含有纤维缠结的神经元数量也明显降低了（P=0.0103）。通过在小鼠右侧海马注射表达P301S突变Tau蛋白的慢病毒载体，研究者们观察到表达APOE4的小鼠左侧海马Tau蛋白病理阳性的神经元数量增加，在神经元内敲除APOE4后有明显改善（P<0.0001）。说明APOE4在Tau蛋白异常磷酸化，Tau蛋白聚集，和Tau蛋白在神经元间传播过程中全部发挥了作用。图a，b: PS19-fE4小鼠中磷酸化Tau和神经纤维缠结较PS19-fE3小鼠明显增加，在神经元中敲除APOE4后下降。图c，d：在右侧海马注射P301S Tau表达载体后，fE4小鼠左侧海马人源性Tau蛋白和磷酸化Tau蛋白均高于敲除组。图e.f：APOE4存在时海马中不可溶性磷酸化Tau蛋白增加。 Tau蛋白病理与AD的进展密切相关，那么，如果在神经元内特异性敲除APOE4是否能改变这一进程呢？研究者们对此一一进行了解答。首先，研究发现PS19-fE4小鼠海马区发生了神经退行性改变,这一组小鼠的海马体积显著缩小，海马CA1区和齿状回的厚度明显变薄，神经元凋亡标志物Caspase-3剪切体表达明显升高（P<0.0001），这说明神经元出现了严重的死亡情况。而PS19-fE3，PS19-fE3/Syn1-Cre和PS19-fE4/Syn1-Cre三组小鼠均未出现明显的神经元死亡情况，说明上述神经退行性改变是由于APOE4存在引起的。图a，b: PS19-fE4小鼠海马体积减小，齿状回厚度降低，敲除神经元APOE4后恢复。图c，d：PS19-fE4小鼠海马出现神经脱髓鞘改变和神经元过度兴奋，敲除神经元APOE4后恢复。在髓鞘损伤的检测中也有类似的发现。研究人员检测了PS19-fE4小鼠海马区髓鞘损伤情况和髓鞘修复情况。结果发现APOE4存在的情况下小鼠髓鞘受损严重。在海马区特异性敲除APOE4后，髓鞘受损情况和损伤修复情况均恢复到了与PS19-fE3小鼠相似的水平。除此之外，研究者们还发现与PS19-fE3小鼠相比，PS19-fE4小鼠CA1-CA3环路过度兴奋，小胶质细胞和星形胶质细胞明显激活。APOE4敲除后这两种现象都得到了缓解。由此可见，神经元内APOE4的敲除减缓了Tau蛋白病理状态下的神经元死亡、神经系统脱髓鞘改变和神经元功能的改变。通过上述结果，我们不难发现，神经元内APOE4的存在不仅影响了神经元本身，还影响了胶质细胞。那么在整个海马区域，是不是所有细胞都受到了这种影响，共同推动了神经退行性改变的进展呢？接下来的实验中，研究者们对PS19-fE3，PS19-fE4，PS19-fE4/Syn1-Cre三组小鼠海马区的细胞进行了单细胞核转录组分析，根据不同的细胞标记基因表达水平变化，将整个海马区的细胞分成了34个类群。根据每群细胞在三组小鼠中数量占比的不同，研究者们将在PS19-fE4小鼠中显著增加的细胞群定义为神经元APOE4介导的疾病相关(nE4-DA)细胞群。图a: 单细胞核转录组分析将海马细胞分为34个亚群。图b: 三组小鼠中不同亚群细胞中APOE表达情况。图c：疾病相关神经元中高表达和低表达的基因。图d：PS19-fE4/Syn1-Cre小鼠与PS19-fE4小鼠相比疾病相关神经元中基因表达的变化情况。在对这些特殊细胞群进行基因表达分析时，研究人员有了令人兴奋的发现。不论什么种类的细胞中，nE4-DA细胞群均高表达Hspa8，Hsp90aa1，Hsp90ab1，Calm1，Calm2，Nrgn和Ubb这几种基因。不仅如此，通过对PS19-fE4/Syn1-Cre小鼠的nE4-DA细胞群进行分析，研究者们发现清除神经元中的APOE4基因后，上述基因表达量降低了。这说明APOE4的清除不仅改变了nE4-DA细胞群的数量，还改变了nE4-DA细胞群的基因表达。这些在APOE4存在情况下高表达的基因，可能就是解开APOE4致病机制之谜的关键。总的来说，本研究重点关注了神经元中APOE4对Tau蛋白病理的推动作用，发现神经元中特异性敲除APOE4可以使海马中的病理性Tau蛋白含量下降81%。尽管神经元中的APOE4如何介导其它细胞的病理变化还有待探索，但本文已经为我们提供了很有利的证据。如果能够找到安全稳定的方法特异性敲除神经元中的APOE4基因，也许能够降低这类人群的患病风险。参考文献： [1] Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-923. doi:10.1126/science.8346443 [2] Koutsodendris, N., Blumenfeld, J., Agrawal, A. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging (2023). https://doi.org/10.1038/s43587-023-00368-3 [3] Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523-527. doi:10.1038/nature24016