A Phase I Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma, Transformed Follicular Lymphoma, Other Non-Hodgkin's Lymphomas, Solid Tumors and Multiple Myeloma

This is an open-label, multicenter, 2-part study to determine the recommended Phase 2 dose (RP2D) for GSK2816126 given twice weekly by intravenous (IV) infusion. Part 1 will be conducted in adult subjects with relapsed/refractory diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), other Non-Hodgkin's lymphomas (NHL), solid tumors (including castrate resistant prostate cancer) and multiple myeloma (MM) to determine the safety and tolerability of GSK2816126. Expansion cohorts (Part 2) are planned to further explore clinical activity of GSK2816126 at the RP2D in subjects with Enhancer of Zeste 2 (EZH2) wild type and EZH2 mutant positive germinal center B-cell like diffuse large B cell lymphoma (GCB-DLBCL), tFL and MM.

开始日期2014-04-24

申办/合作机构

GSK Plc

100 项与 GSK-2816126 相关的临床结果

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100 项与 GSK-2816126 相关的转化医学

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100 项与 GSK-2816126 相关的专利（医药）

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359

项与 GSK-2816126 相关的文献（医药）

2025-05-01·BRITISH JOURNAL OF HAEMATOLOGY

The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8⁺ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia

Article

作者: Wang, Wenjing ; Chen, Xiuhua ; Hou, Yanfei ; Feng, Mengjing ; Zheng, Zhuanzhen ; Ren, Fanggang

Summary:

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) link to unfavourable prognoses. We explored the mechanism of enhancer of zeste homologue 2/histone H3 of lysine 27 (EZH2/H3K27me3) downregulating C‐X‐C motif chemokine 10 (CXCL10) to affect CD8+ T‐cell exhaustion, participating in MDS‐to‐AML transformation. NHD13 mice were treated with GSK126 (EZH2 inhibitor) and CXCL10 neutralizing antibody, with transformation time, blood cell counts and CD8+ T cell determined. SKM‐1 cells treated with short hairpin‐EZH2, overexpressing‐EZH2, GSK126 and CXCL10 were co‐cultured with CD8+ T cells. EZH2, CXCL10, H3K27me3 and EZH2 levels and EZH2 enzyme activity were assessed. CD8+ T‐cell cytotoxicity, exhaustion, apoptosis and SKM‐1 cell malignant behaviours were evaluated. In vivo, EZH2 inhibition upregulated CXCL10, decelerating MDS to AML transformation and delaying CD8+ T‐cell exhaustion. EZH2 inhibition elevated peripheral blood cells, alleviated splenomegaly, reduced CD8+ T cells, elevated CD8+ T cytotoxicity and abated CD8+ T‐cell exhaustion in NHD13 mice. CXCL10 neutralizing antibody accelerated AML transformation by inhibiting CD8+ T‐cell exhaustion via EZH2. In vitro, EZH2 overexpression facilitated CD8+ T‐cell exhaustion and SKM‐1 cell malignant behaviours. EZH2‐mediated H3K27me3 curbed CXCL10 transcription and secretion. Collectively, EZH2/H3K27me3 downregulates CXCL10 to facilitate CD8+ T‐cell exhaustion, accelerating transformation from MDS to AML.

2025-04-01·iScience

Dual targeting of CXCR4 and EZH2 in endometriosis

Article

作者: Wagner, Kassey ; Santanam, Nalini ; Ruley, Morgan ; Mitchell, Brenda ; Brunty, Sarah ; Fleshman, Taylor

We recently showed that endometriotic peritoneal fluid (PF) altered the regulation of enhancer of zeste homolog 2 (EZH2) and H3K27me3. This study aimed to determine if PF by regulating EZH2/H3K27me3 modulated C-X-C chemokine receptor type 4 (CXCR4), a major chemokine involved in the proliferation and migration processes in endometriosis. Endometriotic PF induced the mRNA expression of CXCR4 and EZH2 and protein expression of H3K27me3 in human endometrial stromal cells (hESCs) and eutopic endometrium (Eu). CXCR4 inhibitor, AMD3100, decreased the PF-induced expression of these factors and reduced migration, but increased the proliferation of hESCs. In contrast, the EZH2 inhibitor, GSK126, decreased the expression of EZH2 and H3K27me3 and reduced proliferation, but increased the expression of CXCR4 and migration of hESCs. A combination of both inhibitors decreased the expression of CXCR4, EZH2, and H3K27me3, as well as reduced cell proliferation and migration. Our study suggests that targeting both CXCR4 (inflammation) and EZH2 (epigenetics) may be a better alternative for women with endometriosis.

2025-03-01·JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

APN/AdipoRon regulates luteal steroidogenesis through AMPK/EZH2/H3K27me3 in goats

Article

作者: Yu, Hao ; Li, Haolin ; Wang, Wei ; Mao, Dagan ; Pei, Xiaomeng

AMPK plays a crucial role in cellular energy metabolism and is involved in the regulation of luteal steroidogenesis by APN and its analog AdipoRon. To further explore the regulatory mechanism of AMPK in goat luteal steroidogenesis mediated by APN, cyclic and pregnant CL were utilized to assess the localization and expression of AMPK, EZH2, H3K27me3 and H3K27ac by WB and mIHC, and the interaction between AMPK and EZH2 by Co-IP. Then, isolated luteal cells were treated with APN/AdipoRon to evaluate the expression levels of AMPK, EZH2, H3K27me3 and H3K27ac. Results showed that AMPK and EZH2 were co-localized to the cytoplasm of luteal cells, and interacted as detected by Co-IP. H3K27me3 and H3K27ac were localized to the nucleus of goat luteal cells. H3K27me3 expression in late CL was significantly higher than that in early and middle CL, while the expressions of AMPK, H3K27ac and EZH2 in middle CL were significantly higher than those in early and late CL. Notably, all these proteins were expressed at similar levels between pregnancy and middle cycle, with the exception of EZH2. Following incubation with AdipoRon (25 μM) and APN (1 μg/mL) for 24 h, the expressions of AMPK and H3K27ac decreased, while H3K27me3 increased in luteal cells. Compound C (AMPK activity inhibitor) reversed the AdipoRon - induced decrease in EZH2 expression and the increase in H3K27me3 expression. The increased H3K27me3 expression and decreased steroidogenic protein (CYP11A1 and HSD3B) expression after GSK126 (EZH2 inhibitor) treatment were consistent with the effects seen after AdipoRon treatment. In conclusion, APN/AdipoRon inhibits luteal steroidogenesis by inhibiting the interaction between AMPK and EZH2, thereby promoting H3K27me3 expression.

项与 GSK-2816126 相关的新闻（医药）

2024-10-15

·CPHI制药在线

辉瑞重磅新药启动III期临床研究，有望成为前列腺癌一线疗法EZH2抑制剂！

关注并星标CPHI制药在线近日，中国药物临床试验登记与信息公示平台官方网站予以公示，辉瑞（Pfizer）已然开启了一项国际多中心（涵盖中国）的 III期临床研究，此研究旨在评估 PF -06821497(Mevrometostat)联合恩扎卢胺相较于恩扎卢胺或者多西他赛针对既往经受过醋酸阿比特龙治疗的转移性去势抵抗性前列腺癌患者的疗效及安全性。依据公示内容，该研究计划于国际范围纳入 600 人，在我国国内纳入90人。对于此项研究，辉瑞的愿景是构建全新的一线 mCRPC 标准治疗方案，以延长患者的生存期限。 Mevrometostat乃是辉瑞研发的一款 EZH2 抑制剂，其能够阻断癌细胞中因 EZH2 过度表达所驱动的非正常基因表达，从而致使癌细胞增殖降低、诱导细胞死亡，并且抑制癌细胞的迁移与侵袭，最终实现治疗癌症的目标。在此之前辉瑞宣称，这款药物有希望成为在美国获得批准的首款用于前列腺癌的 EZH2 抑制剂。据今年 3月辉瑞在其肿瘤学创新日期间所披露的情况，到 2030 年其肿瘤学研发管线有望推出超过8 款重磅疗法，当中便包含这一EZH2抑制剂。截图来源：中国药物临床试验登记与信息公示平台官网截图来源：Clinicaltrials官网一、EZH2：癌症治疗的新靶点目前，EZH2已然跻身癌症治疗的前沿靶点队列之中。EZH2属于一种组蛋白甲基转移酶，其异常的表达与众多癌症的发展以及不良预后存在关联，像前列腺癌、乳腺癌、肺癌以及血液恶性肿瘤等均涵盖在内。有研究指出，EZH2的过度表达能够凭借多种作用机制推动癌症的产生和发展，涵盖了使肿瘤抑制基因的表达受到抑制、促使参与细胞增殖以及存活的基因进行表达等。另外，EZH2已获证实能够通过调控参与上皮-间质转化的基因表达来助推癌症转移。举例来讲，他泽司他（tazemetostat）已经获批用于部分类型血液肿瘤的治疗。与此同期，全球范围内尚有众多的EZH2抑制剂正在进行研发工作，用于诊治多种不同类别的肿瘤。 EZH2在引发GBM癌细胞侵袭、迁移和增殖以及维系其干细胞特性的过程里发挥着关键效用。组蛋白的甲基化、乙酰化、泛素化和磷酸化等修饰将DNA编排成核小体，和正常细胞的功能以及肿瘤的发生有所关联。EZH2的过表达或者突变（像是淋巴瘤里的功能获得性突变以及髓系恶性肿瘤里的功能丧失性突变）已经在诸多肿瘤中被确认，使得EZH2成为潜在的治疗目标。已经鉴别出数种调节EZH2的机制，包含miRNA、LncRNA对EZH2mRNA的调节、翻译后的修饰、转录的调控以及通过DNA结合蛋白的DNA可及性。例如，miR-124-3p表达的增高致使mTOR和AKT磷酸化水平下降，而miR-124-3p表达的降低则产生相反效果。研究成果显示，miR-124-3p通过瞄准EZH2抑制前列腺癌的增殖和侵袭进程，同时引导细胞凋亡。 lncRNA被界定为一类长度大概为200个核苷酸、不存在显著蛋白质编码能力的RNA分子。lncRNA和癌症的进展存在关联，例如细胞侵袭、迁移和血管生成以及自噬。比如，已知HOTAIR是不同类别癌症临床结局的预测因子。LnRNA HOTAIR能够作为PRC2和不同组蛋白修饰的模块化支架。研究表明，lncRNA 调节 EZH2 基因的功能和表达。EZH2 还调节参与多种致癌信号通路的几种 lncRNA 的转录。 EZH2信号通路驱动癌症进展，并有可能干扰抗肿瘤免疫反应，因此它作为癌症治疗的有效治疗靶点而受到关注。通过使用EZH2-CRISPR/Cas9，HIF-1α被表观遗传抑制，导致癌症类型的免疫抑制作用停止或减弱。研究结果表明，利用纳米颗粒递送的EZH2 siRNA可以通过下调EZH2表达有效降低肿瘤细胞的侵袭和迁移能力，并可对卵巢癌细胞和肺癌细胞产生协同治疗作用。小发夹RNA是另一种可以在癌症治疗中抑制EZH2存在的RNA干扰。例如，通过shRNA降低EZH2水平可以降低前列腺癌细胞的转移和增殖率。因此，遗传方法为在癌症治疗中靶向和调节EZH2表达提供了一种有希望的途径。EZH2 抑制剂包括 GSK2816126、Tazemetostat、Valemetostat、cPI-0209、SHR2554、MAK683 和 PF-06821497，它们可抑制其功能并恢复致癌转录因子。二、Mevpro临床研究这是一项全球性、多中心且随机的 III期研究（Mevpro-2），用以对Mevrometostat 联合恩杂鲁胺以及安慰剂联合恩杂鲁胺于 mCRPC 患者之中的疗效展开评估，此类患者在被确诊 mCRPC 之后，除了 ADT （雄激素剥夺疗法）和第一代抗雄激素药物之外，未曾接受过其他的全身抗癌治疗。这项临床研究在日本和美国开启。另外，在8 月份，辉瑞于中国、美国等众多国家首次开启了一项有关 Mevrometostat的 III 期研究（MEVPRO-1），将恩扎卢胺联合恩扎卢胺或多西他赛用于既往已接受过醋酸阿比特龙治疗的转移性去势抵抗性前列腺癌患者。对于该研究，其目的在于延长恩扎卢胺的疗效，并取代化疗。截图来源：辉瑞肿瘤创新日资料有关研究指出，EZH2对基因活性起到参与调控的作用，和前列腺癌细胞的增殖存在关联。临床前的相关数据表明，Mevrometostat 能够抑制基因调控，并且和恩扎卢胺具备协同功效。源自辉瑞公开的临床成果，Mevrometostat与恩扎卢胺联合的1 期临床呈现出良好的抗肿瘤活性。在此之中，Mevrometostat联合恩扎卢胺针对既往接受过阿比特龙治疗的 mCRPC 患者，其中位放射学无进展生存期（rPFS）达 17.1 个月，对比以往的数据（中位 rPFS 为4.8个月），获益颇为显著；Mevrometostat联合恩扎卢胺对于既往接受过恩扎卢胺治疗的mCRPC患者，其中位rPFS为 11.7 个月。另外，辉瑞在近日还开启了另外一项 3期的 MEVPRO-2研究，这项研究打算评估 mevrometostat加恩扎卢胺对于未经阿比特龙治疗的转移性去势抵抗性前列腺癌男性患者的作用。针对这一适应症的临床研究申请（IND）也已在中国获得批准，预计很快将会在中国开启。三、多款EZH2抑制剂已获批，但适应症不同据Insight 数据库透露，当下全球已有2种药物成功获批得以上市，然而获批的适应症却各不相同。第一款：益普生研发靶向EZH2 他泽司他，其于2020年率先在美国获得批准，当前已经被批准用于上皮样肉瘤、滤泡性淋巴瘤。在 2024年 7月 4日，这款药于中国提交了上市申请（JXHS2400046），其适应症为 EZH2突变呈阳性且之前接受过至少两种系统性治疗的复发或者难治性滤泡性淋巴瘤(FL)成年患者，预计会在 2025年第二季度获批。第二款：第一三共研发且靶向 EZH1/EZH2 的 Valemetostat，它在2022 年最先于日本获批上市，当前已批准用于成人 T细胞白血病-淋巴瘤、外周 T细胞淋巴瘤；在国内的研发处于批准临床的阶段。辉瑞的 Mevrometostat 在 mCRPC 适应症方面于全球的进展可谓最快，倘若一切顺利，或许会成为全球首款获批用于前列腺癌的 EZH2 抑制剂。国内的企业在 EZH2靶点上也并未落后太多，当下共有 4款国产的EZH2抑制剂迈入了临床阶段。其中恒瑞的进展最为迅速，SHR2554已经进入了III 期临床，其适应症为外周 T 细胞淋巴瘤，该临床被 CDE授予了突破性疗法认定以及特殊审批。参考资料： [1] 中国药物临床试验登记与信息公示平台官网.Retrieved Oct 8，2024.?From http://www.chinadrugtrials.org.cn/index.html [2]Oncology Innovation Day. Retrieved March 1, 2024, from https://s28.q4cdn.com/781576035/files/doc_downloads/2024/02/29/Pfizer-Oncology-Innovation-Day-Presentation_FINAL.pdf [3]ClinicalTrials官网. From?https://clinicaltrials.gov/search?term=Mevrometostat END 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床3期临床结果临床成功

2023-11-23

·SYNAPSE

What are EZH2 inhibitors and how do you quickly get the latest development progress?

EZH2, also known as enhancer of zeste homolog 2, is an enzyme that plays a crucial role in regulating gene expression and cell differentiation. It belongs to the polycomb group protein family and is involved in the addition of methyl groups to histone proteins, leading to gene silencing. EZH2 is particularly important in embryonic development and tissue regeneration, as it helps maintain stem cell pluripotency and controls cell fate determination. Dysregulation of EZH2 has been implicated in various diseases, including cancer, where it can promote tumor growth and metastasis. Targeting EZH2 has emerged as a potential therapeutic strategy in the pharmaceutical industry for the treatment of certain cancers. EZH2 inhibitors can enhance the function of CD8+ T effector cells, promote the secretion of chemoattractants by tumor-infiltrating DC cells, and facilitate the migration of effector T cells to the tumor microenvironment (TME). EZH2 inhibitors decrease the lineage stability of Tregs and suppress their function, thereby overcoming drug resistance problems related to immune checkpoint inhibitors to some extent. EZH2 inhibitors promote the maturation, activation, and activation receptor expression of NK cells, boosting the inherent immunity against tumors. Additionally, EZH2 inhibitors can enhance the antigen presentation capability of the tumor microenvironment, triggering the activation of adaptive immune responses against tumors. The analysis of the current competitive landscape of target EZH2 reveals that multiple companies are actively involved in the research and development of drugs targeting this target. Ipsen SA, Daiichi Sankyo Co., Ltd., and Jiangsu Hengrui Pharmaceutical Group Co. Ltd. are among the companies with the highest stage of development on this target. Drugs targeting EZH2 have been approved for indications such as Follicular Lymphoma, Sarcoma, Adult T-Cell Leukemia-Lymphoma, and Lymphoma. Small molecule drugs are progressing rapidly, with intense competition from biosimilars. China is showing significant progress in the development of drugs targeting EZH2. The future development of target EZH2 is promising, with ongoing research and development efforts by various companies and countries/locations. EZH2 Inhibitors: A Promising Novel Approach in Cancer TherapeuticsEZH2 inhibitors are a type of drug that target and inhibit the activity of the EZH2 enzyme. EZH2, or Enhancer of Zeste Homolog 2, is a protein involved in the regulation of gene expression and plays a role in various cellular processes, including cell growth and differentiation. From a biomedical perspective, EZH2 inhibitors are of particular interest in the field of cancer research. EZH2 is often overexpressed in various types of cancer, including prostate, breast, and lymphomas. Overexpression of EZH2 can lead to abnormal gene silencing and promote tumor growth. By inhibiting the activity of EZH2, these inhibitors aim to restore normal gene expression patterns and potentially slow down or stop the growth of cancer cells. EZH2 inhibitors are being investigated as potential therapeutic agents in preclinical and clinical studies. Some examples of EZH2 inhibitors include tazemetostat and GSK126. These inhibitors have shown promise in early studies and are being evaluated for their efficacy and safety in treating different types of cancer. Catalog of EZH2 InhibitorsThe currently marketed EZH2 inhibitors include: Valemetostat TosilateTazemetostat HydrobromideSHR-2554XNW-5004HH-2853TulmimetostatAXT1003HM-97662PF-06821497TR115For more information, please click on the image below. What is the purpose of using EZH2 inhibitors?EZH2 inhibitors have been approved for indications such as Follicular Lymphoma, Sarcoma, Adult T-Cell Leukemia-Lymphoma, and Lymphoma. For more information, please click on the image below to log in and search. How to acquire the most recent advancement in EZH2 inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of EZH2 inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

2022-11-18

·生物制药小编

肿瘤新型治疗靶点：EZH1/2

EZH2及其高度相关的同源基因EZH1被认为是表观遗传沉默因子，它们作为多梳抑制性复合体2(PRC2)的核心成分，在细胞的生长和分化中起着关键作用。EZH1和EZH2在人类恶性肿瘤中起作用，这两个基因的变化与人类恶性肿瘤的转化有关。抑制EZH1/2已被证明可导致人类肿瘤的消退，并已在临床前和多个临床试验中进行了研究和评估。本文就EZH1/2的结构与功能、与肿瘤进展的关系以及靶向EZH1/2抑制剂的临床概况做一个简要介绍，旨在阐明EZH1/2作为肿瘤治疗靶点的意义。EZH1/2的结构与功能 PRC2是一种多蛋白转录抑制复合物，包含四个核心成分: EZH2及其高度相关的同源物EZH1、胚胎外胚层发育的抑制子(EED)、zeste 12的抑制子(SUZ12)和视网膜母细胞肿瘤相关蛋白46和48 (RbAp46/48) (图1)。这些主要的核心成分与一些其他非核心组件结合，以进行单甲基化、二甲基化和三甲基化，从而促进染色质致密化并实现靶基因的转录抑制，其涉及发育、组织稳态的调节和谱系特异性。图1. PRC2复合物EZH1包含EZH1α和EZH1β两种异构体。EZH1α定位于细胞核，而EZH1β定位于分化的肌肉细胞胞浆基质。EZH1α全长747个氨基酸，从N-端到C-端的主要功能区是WD结构域(WD-40结合区)、SANT1(SWI3-ADA2-N-COR-TFIIIB)结构域、SANT2结构域、CXC(半胱氨酸区)结构域和SET结构域(图2)。WD和SANT1结构域的主要功能是与EED结合，SANT2、CXC和SET是与SUZ12结合。此外，CXC和SET结构域也是催化区。与EZH1α不同，EZH1β在C末端没有催化区域。EZH1β在骨骼肌中的作用是通过与细胞质中的EED靶基因结合来阻止EED、SUZ12和EZH1α在细胞核中的组装，从而控制PRC2-EZH1的活性以响应萎缩的氧化应激。总之， EZH1β间接调节PRC2-EZH1α在细胞核内的组装和功能。图2. EZH1α和EZH1β结构EZH2没有和EZH1一样的异构体，只有571个氨基酸的N-端到C-端结构。EZH2的结构域分为三个主要部分，第一部分是SDB，EBD，BAM，SAL，SRM，SANT1，中间部分是MCSS和SANT2，第三部分是催化CXC和SET结构域 (图3)。EZH2主要定位于胞核，但已有研究人员提出EZH2在细胞质中的作用，即在三阴性乳腺癌细胞中，T367处磷酸化的EZH2(pT367-EZH2)与胞浆蛋白结合，促进肿瘤侵袭和转移。图3. EZH2结构EZH1和EZH2之间存在的结构相似性和差异，导致了它们的功能相似性和差异。EZH1和EZH2在细胞发育和分化过程中以相反的方式表达，EZH2主要在增殖细胞中表达，而EZH1在有丝分裂后的细胞中表达。虽然EZH1具有较弱的组蛋白甲基转移酶(HMTase)活性，在缺乏EZH2的情况下，它可以取代EZH2，将基础H3K27me3水平维持在PRC2的靶向水平，并促进染色质致密化（图4）。图4. EZH1和EZH2对H3K27me3的调控肿瘤学中的EZH1EZH1基因在肿瘤中的异常在常见肿瘤中， EZH1的表达低于正常组，只有少数肿瘤高表达。EZH1在套细胞淋巴瘤、乳腺癌、T细胞淋巴瘤和胃癌、肝细胞癌以及胆管细胞癌观察到高表达，而突变主要为滤泡型甲状腺肿瘤。EZH1与诊断及预后的关系EZH1在一些肿瘤中的高表达与其诊断和预后有关，如乳腺癌、胃癌、结直肠癌、肝细胞癌。此外，Chakraborty的团队指出，von Hippel-Lindau肿瘤抑制蛋白(PVHL)的失活是肾透明细胞癌(ccRCC)的标志性病变，而pVHL缺陷的ccRCC细胞高度依赖H3K27甲基转移酶EZH1生存。因此，靶向EZH1可能对慢性肾细胞癌有治疗作用。EZH1除了在EZH1高表达肿瘤中作为诊断标志物的潜力外，在套细胞淋巴瘤等肿瘤中，当EZH2功能失活或耗尽时，EZH1代偿性增加所造成的预后不良也不容忽视。EZH1在肿瘤发生、发展和治疗中的生物学作用EZH1的过度表达与抑制细胞凋亡蛋白和诱导细胞周期蛋白有关。抑制细胞凋亡过程但促进细胞周期蛋白的表达可导致细胞不受控制的增殖，即癌变，提示EZH1与肿瘤生长之间存在联系。一些microRNA如microRNA-370-5p、microRNA-20a、microRNA-182-5p等可直接靶向EZH1，参与肿瘤生长、侵袭潜能和细胞凋亡等生物学过程的调控。此外，由于EZH2基因的突变或肿瘤细胞中EZH2特异性抑制剂的治疗后，EZH1的代偿作用将在很大程度上被激发，从而也可以维持一个良好的肿瘤发展环境。总体而言，EZH1在大多数肿瘤中的作用主要是维持H3K27me3的水平，以确保在EZH2失活或耗尽的情况下转录沉默模式的正常功能。因此，为了最大限度地发挥EZH2小分子抑制剂的作用，即要完全抑制EZH2的功能，又要抑制EZH1的代偿作用。肿瘤学中的EZH2EZH2基因在肿瘤中的异常表达通常情况下，EZH2在大多数人类实体肿瘤中过表达。EZH2的低表达或突变在血液肿瘤中更为常见。研究表明，在超过20%的弥漫性大B细胞淋巴瘤(DLBCL)和7%的滤泡性淋巴瘤(FL)中，已经检测到EZH2酪氨酸641位的功能性获得突变(Y641N和Y641F) ，但在实体瘤中很少发现。EZH2与诊断及预后的关系EZH2的过度表达与大多数肿瘤的侵袭性、不良预后和复发有关。由于其酶活性，EZH2可以与靶基因的启动子结合，诱导甲基化并影响其表达。EZH2有助于促进肿瘤进展，并影响宫颈癌、三阴性乳腺癌、结直肠癌等肿瘤患者的总体生存(OS)和无进展生存(PFS)，这揭示EZH2可作为大多数肿瘤的诊断标记物。EZH2普遍被认为是一种肿瘤促进因子，然而，一些研究报道，EZH2也可能在实体肿瘤中发挥肿瘤抑制作用，如胃癌、髓母细胞瘤。这些表明，EZH2发挥相反的作用并不是因为实体瘤和血液瘤的区别，而是因为还有其他原因有待探索。总体而言，在大多数肿瘤中，EZH2可被认为与诊断和预后呈正相关。EZH2在肿瘤发生、发展和治疗中的生物学作用EZH2主要参与癌细胞增殖和侵袭的增加。例如，EZH2水平升高通常与细胞周期停滞抑制、凋亡和自噬抑制、肿瘤细胞侵袭和迁移能力增强有关。具体地说，EZH2在肝细胞癌、非小细胞肺癌和套细胞淋巴瘤中的高表达被发现抑制自噬、细胞周期停滞和细胞凋亡。EZH2被报道在脑瘤、鼻咽癌、葡萄膜黑色素瘤、肾透明细胞癌中诱导了细胞侵袭和迁移。此外，在结直肠癌中发现了细胞干性的调节。针对EZH1/2的临床抑制剂EZH2和EZH1蛋白作为表观遗传沉默因子，在细胞的不同发育阶段发挥着重要作用。尽管它们在表观遗传上使肿瘤促进基因和肿瘤抑制基因沉默，但它们的高表达也以不同的比率导致不同的癌症亚型。因此，研究者合成了多种EZH1/2特异性抑制剂，其中部分已进入临床研究。例如， EZH2抑制剂：CPI-0209(Constellation Pharmaceuticals)、CPI-1205(Constellation Pharmaceuticals)、Tazemetostat (Epizyme)、GSK2816126(GSK)和SHR2554(江苏恒瑞医药)。EZH1和EZH2双抑制剂包括Ezharmia(DS-3201b，Daiichi Sankyo)、PF-06821497(Pfizer)和HH2853(Haihe Biopharma)。除了FDA以及MHLW批准的Tazemetostat 和 Ezharmia外，其他药物目前正在进行临床评估(图5)。图5. EZH1/2抑制剂EZH1/2抑制剂与其他药物的联合应用由于单一疗法的局限性，目前许多临床试验使用两种或两种以上药物组合使用(图6)。例如，Epizyme开发tazemetostat已经进行了12项临床试验，并将tazemetostat与其他各种药物联合使用。EZH1/2双抑制剂DS3201b联合伊立替康目前正在招募小细胞肺癌患者进行I/II期临床试验(NCT03879798)。图6. EZH1/2抑制剂与其他药物联合应用的临床试验小编小结 EZH1/2的过度表达或功能突变会扰乱正常的PRC2功能，再加上EZH1和EZH2的相互补偿和替代作用，从而导致肿瘤细胞异常生长、粘附性和侵袭性增加，从而不利于患者生存。因此，EZH1/2在靶向治疗中具有重要意义。由于仅使用EZH2特异性抑制剂的临床疗效不佳，现有的治疗集中在了联合治疗或寻找有效治疗的双重抑制剂。目前，对EZH1和EZH2的双重抑制以及靶向和非靶向组合正在联合进行临床研究，结果是令人振奋的。我们期待后续更多的临床进展，希望这些药物可以早日造福于患者。参考文献EZH1/2 as targets for cancer therapy.Targeting excessive EZH1 and EZH2 activities for abnormal histone methylation and transcription network in malignant lymphomas.

临床结果

100 项与 GSK-2816126 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
去势抵抗性前列腺癌	临床1期	美国	GSK Plc	2014-04-24
去势抵抗性前列腺癌	临床1期	法国	GSK Plc	2014-04-24
去势抵抗性前列腺癌	临床1期	英国	GSK Plc	2014-04-24
弥漫性大B细胞淋巴瘤	临床1期	美国	GSK Plc	2014-04-24
弥漫性大B细胞淋巴瘤	临床1期	法国	GSK Plc	2014-04-24
弥漫性大B细胞淋巴瘤	临床1期	英国	GSK Plc	2014-04-24
滤泡性淋巴瘤	临床1期	美国	GSK Plc	2014-04-24
滤泡性淋巴瘤	临床1期	法国	GSK Plc	2014-04-24
滤泡性淋巴瘤	临床1期	英国	GSK Plc	2014-04-24
多发性骨髓瘤	临床1期	美国	GSK Plc	2014-04-24

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02082977 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	血液疾病 \| 实体瘤	41	GSK2816126	膚築觸淵簾鑰鏇網鹽糧(廠艱網範膚襯齋膚鏇襯) = 構顧鬱餘網憲憲蓋積願製艱構願窪鑰鹽選夢衊 (廠醖窪簾顧築淵願壓鹹 ) 更多	积极	2019-12-15