更新于：2024-05-01

GLS1

谷氨酰胺酶

更新于：2024-05-01

基本信息

别名

GLS、GLS1、glutaminase

+ [6]

简介

Lacks catalytic activity. Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30575854, PubMed:30239721, PubMed:30970188).

关联

项与 GLS1 相关的药物

JAB-24114

靶点

GLS1

作用机制

谷氨酰胺酶抑制剂 [+1]

在研机构

JACOBIO PHARMACEUTICALS GROUP CO., LTD. [+1]

原研机构

JACOBIO PHARMACEUTICALS GROUP CO., LTD.

在研适应症

实体瘤 [+3]

非在研适应症-

最高研发阶段临床申请批准

首次获批国家/地区-

首次获批日期1800-01-20

LTX-001

靶点-

作用机制

GLS1 调节剂

在研机构

Leal Therapeutics LLC

原研机构

Leal Therapeutics LLC

在研适应症

肌萎缩侧索硬化 [+2]

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

HYL-001

靶点

GLS1

作用机制

谷氨酰胺酶抑制剂

在研机构

华中科技大学

原研机构

华中科技大学

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 GLS1 相关的临床结果

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100 项与 GLS1 相关的转化医学

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0 项与 GLS1 相关的专利（医药）

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2,607

项与 GLS1 相关的文献（医药）

2024-02-19·Cell death & disease

Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.

Article

作者: Liangsong Zhu ; Yilun Hong ; Ziran Zhu ; Jiwei Huang ; Jianfeng Wang ; Ge Li ; Xiaoyu Wu ; Yonghui Chen ; Yunze Xu ; Liang Zheng ; Yiran Huang ; Wen Kong ; Wei Xue ; Jin Zhang

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

2024-02-16·Cell death and differentiation

Set7/9 aggravates ischemic brain injury via enhancing glutamine metabolism in a blocking Sirt5 manner.

Article

作者: Jinghuan Wang ; Subei Tan ; Yuyu Zhang ; Jie Xu ; Yuhui Li ; Qianwen Cheng ; Chen Ding ; Xinhua Liu ; Jun Chang

The aberrant expression of methyltransferase Set7/9 plays a role in various diseases. However, the contribution of Set7/9 in ischemic stroke remains unclear. Here, we show ischemic injury results in a rapid elevation of Set7/9, which is accompanied by the downregulation of Sirt5, a deacetylase reported to protect against injury. Proteomic analysis identifies the decrease of chromobox homolog 1 (Cbx1) in knockdown Set7/9 neurons. Mechanistically, Set7/9 promotes the binding of Cbx1 to H3K9me2/3 and forms a transcription repressor complex at the Sirt5 promoter, ultimately repressing Sirt5 transcription. Thus, the deacetylation of Sirt5 substrate, glutaminase, which catalyzes the hydrolysis of glutamine to glutamate and ammonia, is decreased, promoting glutaminase expression and triggering excitotoxicity. Blocking Set7/9 eliminates H3K9me2/3 from the Sirt5 promoter and normalizes Sirt5 expression and Set7/9 knockout efficiently ameliorates brain ischemic injury by reducing the accumulation of ammonia and glutamate in a Sirt5-dependent manner. Collectively, the Set7/9-Sirt5 axis may be a promising epigenetic therapeutic target.

2024-02-14·Molecular carcinogenesis

Glutaminase potentiates the glycolysis in esophageal squamous cell carcinoma by interacting with PDK1.

Article

作者: Guangzhao Zhu ; Fangxia Guan ; Shenglei Li ; Qing Zhang ; Xueying Zhang ; Yue Qin ; Zhangzhan Sun ; Shaohua Peng ; Jiexing Cheng ; Yiyang Li ; Ruili Ren ; Tianli Fan ; Hongtao Liu

Increasing evidence has demonstrated that glutaminase (GLS) as a key mitochondrial enzyme plays a pivotal role in glutaminolysis, which widely participates in glutamine metabolism serving as main energy sources and building blocks for tumor growth. However, the roles and molecular mechanisms of GLS in esophageal squamous cell carcinoma (ESCC) remains unknown. Here, we found that GLS was highly expressed in ESCC tissues and cells. GLS inhibitor CB-839 significantly suppressed cell proliferation, colony formation, migration and invasion of ESCC cells, whereas GLS overexpression displayed the opposite effects. In addition, CB-839 markedly suppressed glucose consumption and lactate production, coupled with the downregulation of glycolysis-related proteins HK2, PFKM, PKM2 and LDHA, whereas GLS overexpression exhibited the adverse results. In vivo animal experiment revealed that CB-839 dramatically suppressed tumor growth, whereas GLS overexpression promoted tumor growth in ESCC cells xenografted nude mice. Mechanistically, GLS was localized in mitochondria of ESCC cells, which interacted with PDK1 protein. CB-839 attenuated the interaction of GLS and PDK1 in ESCC cells by suppressing PDK1 expression, which further evoked the downregulation of p-PDHA1 (s293), however, GLS overexpression markedly enhanced the level of p-PDHA1 (s293). These findings suggest that interaction of GLS with PDK1 accelerates the glycolysis of ESCC cells by inactivating PDH enzyme, and thus targeting GLS may be a novel therapeutic approach for ESCC patients.

项与 GLS1 相关的新闻（医药）

2024-02-21

·今日头条

新靶点！上海交大发文：揭示肾细胞癌治疗新策略

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：富马酸水解酶(FH)缺陷型肾细胞癌(RCC)是一种具有明确代谢紊乱的肿瘤，但其代谢重塑机制尚不清楚。 2月19日，上海交通大学研究团队在期刊《Cell Death&Disease》上发表了题为“Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma”的研究论文，本研究中，研究人员分析了FH缺陷肾癌样本中的LncRNA和mRNA的表达谱，发现与ccRCC相比，LncRNA- mir4435 - 2GH在FH缺陷肾癌中特异性地高表达。体外实验表明，MIR4435-2HG受富马酸盐通过组蛋白去甲基化调控，该基因的缺失可抑制谷氨酰胺代谢。实验还表明，GLS1抑制剂CB-839能显著抑制PDX肿瘤模型的生长。研究人员发现GLS1是该肿瘤的治疗靶点，MIR4435-2HG可作为药物敏感性标志物。 https://www.nature.com/articles/s41419-024-06510-2 研究背景 01 细胞增殖异常是肿瘤发生发展的基本特征，肿瘤代谢异常也是这一特征的基本表现。众所周知，在肾细胞癌(RCC)的发生发展过程中，参与RCC代谢相关反应的基因有数十个，包括对微环境中氧的感知、铁的摄取以及营养物质的摄取和利用等，其中与葡萄糖代谢相关的最重要的基因是TCA循环中富马酸水解酶(FH)和琥珀酸脱氢酶(SDH)的三羧酸调节。遗传性平滑肌瘤病肾细胞癌(HLRCC)是一种具有FH基因胚系功能缺失突变的更具侵袭性的肾癌。富马酸被证明在细胞转化和肿瘤发生中起关键作用。据报道，富马酸盐还可以作为表观遗传调节剂发挥作用。长链非编码RNA (Long non-coding RNA, LncRNA)是一类长度大于200nt且不具备编码蛋白质能力的RNA，也属于表观遗传的范畴。近年来，随着代谢组学的发展，人们发现LncRNA与肿瘤细胞代谢之间的串扰与肿瘤的进展和转移密切相关，探索它们之间的内在联系非常重要。然而，LncRNA在FH缺陷型肾癌中的代谢调控及促进其恶性进展的具体机制尚不明确，需要进一步研究。研究进展 02 为了找出FH缺陷RCC中特异性的致癌LncRNA，研究人员检测了3对FH缺陷RCC样本和配对正常组织中LncRNA和mRNA的全基因组表达。另外，4例透明细胞RCC (ccRCC)患者的肿瘤和癌旁标本作为对照。研究人员发现LncRNA-MIR4435-2HG在FH缺陷的RCC中特异性高表达，而不是在ccRCC中。研究人员还证明，MIR4435-2HG的高表达与pRCC患者的晚期肿瘤分期和较差的生存率显著相关。此外，体外和体内实验表明，MIR4435-2HG通过促进STAT1/GLS1信号通路，在谷氨酰胺代谢重塑和癌症发展中发挥关键作用，提示通过特异性抑制剂CB-839靶向GLS1可能是治疗FH缺陷RCC的一种有前景的治疗策略。本研究示意图研究结论 03 结合以往体外和体内数据，研究人员认为富马酸盐通过抑制组蛋白去甲基化酶活性激活谷氨酰胺代谢相关酶，从而导致谷氨酰胺代谢重塑。研究表明，GLS1与肿瘤增殖和血管生成有重要关系。目前，几种GLS1抑制剂已用于肿瘤治疗相关的临床试验，并显示出一定的肿瘤抑制作用，包括淋巴瘤、胰腺癌和乳腺癌，但在FH缺乏的RCC中，谷氨酰胺代谢及相关抑制剂的研究尚未得到很好的报道。基于以往数据，研究人员认为谷氨酰胺代谢的重塑在FH缺陷RCC的发展中也起着重要作用，GLS1抑制剂(如CB-839)的应用可能使这些患者受益。MIR4435-2HG将成为GLS1靶向治疗的重要药敏标志物。参考资料： https://www.nature.com/articles/s41419-024-06510-2 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

信使RNA临床研究

2023-10-09

·BioSpace

Newfound Mechanism Suggests Drug Combination Could Starve Pancreatic Cancer

[09-October-2023] NEW YORK, Oct. 9, 2023 /PRNewswire/ -- A new combination of treatments safely decreased growth of pancreatic cancer in mice by preventing cancer cells from scavenging for fuel, a new study finds. Led by researchers at NYU Grossman School of Medicine, its Department of Radiation Oncology, and the Perlmutter Cancer Center, the work builds on prior discoveries at NYU Langone that revealed how pancreatic cancer cells, to avert starvation and keep growing, find alternate fuel sources. Normally supplied by the bloodstream, oxygen, blood sugar, and other resources become scarce as the increasing density of fast-growing pancreatic tumors cuts off their own blood supply. In this environment, the ability to switch fuels contributes to the deadliness of pancreatic cancers. Published online October 9 in Nature Cancer, the new study involves a drug designed to prevent pancreatic ductal adenocarcinoma (PDAC) cells from one such switch. PDAC cells use the enzyme glutaminase to convert the amino acid glutamate into glutamine, a form that can be burned for fuel to sustain rapid tumor growth. Drugs designed to block glutaminase, however, have been shown to cause cancer cells to switch to still other scavenging pathways. For this reason, the field next looked at experimental treatments like DRP-104, designed by Dracen Pharmaceuticals, a new "prodrug" form of the compound 6-Diazo-5-oxo-L-norleucine (DON) that is preferentially activated within tumors to overcome toxicity issues seen with DON. DON was designed to starve cancer cells by mimicking glutamine, which unlike glutaminase blockers, broadly inhibits all metabolic pathways that use glutamine. Currently in clinical trials against non-small cell lung cancer, DRP-104 cannot be burned as fuel, but clings to the same enzymes as glutamine. In the current study, DRP-104 treatment alone decreased PDAC growth in mouse models of pancreatic cancer. Importantly, the current team also found that PDAC cells pushed into metabolic crisis by DRP-104 increase signaling through a protein called extracellular signal-regulated kinase or ERK, to make up for their loss of glutamine metabolism. When the team combined DRP-104 with an existing drug that blocks the ERK signaling pathway, trametinib, it further improved survival in pancreatic cancer mouse models compared to DRP-104 treatment alone. "Despite a decade of advances in understanding how cancer cells switch fuel sources, we have not yet effectively translated this into clinically relevant therapies," says corresponding study author Alec Kimmelman, MD, PhD, the Anita Steckler and Joseph Steckler Chair of Radiation Oncology at NYU Langone Health. "Broad antagonism of metabolic pathways with glutamine analogs may provide another mode of attack against these highly resistant tumor cells. The fact that such drugs are already being tested in the clinic makes us hopeful that we may finally see patient outcomes improve, if this approach proves to be effective in clinical trials." Moving forward, the research team will seek to understand how glutamine antagonism impacts other adaptive nutrient scavenging mechanisms in pancreatic cancers and whether these could be targeted as well. The success of such approaches will depend on careful balancing of improved therapeutic efficacy and toxicity from the potential effects on normal tissues, Kimmelman adds. Along with Kimmelman, authors from Perlmutter Cancer Center and the Department of Radiation Oncology at NYU Langone were Joel Encarnación-Rosado, Albert Sohn, Douglas Biancur, Elaine Lin, Victoria Osorio-Vasquez, and Diana González-Baerga. Also Perlmutter authors were Ende Zhao and Diane Simeone. Also authors of the study were Tori Rodrick and Drew Jones from the Division of Advanced Research Technologies at NYU Grossman School of Medicine; Seth Parker from the Department of Biochemistry & Molecular Biology at University of British Columbia in Vancouver, and Yumi Yokoyama and Robert Wild from Dracen Pharmaceuticals, Inc., of San Diego. Funding for the study came from Perlmutter Cancer Center support grant P30CA016087 and National Cancer Institute grants P01A1080192, P01CA117969, R35CA232124, P30CA016087-38, 1R01CA251726-01A1; as well as from the Lustgarten Foundation, Stand Up to Cancer, and the Howard Hughes Medical Gilliam Fellowships. Kimmelman has financial interests in Vescor Therapeutics, is on the scientific advisory board of Rafael/Cornerstone Pharmaceuticals and OncoRev, and has been a consultant for Deciphera and Abbvie. These relationships are being managed according with the policies of NYU Langone Health. Yokoyama and Wild are employees of, and have ownership in, Dracen Pharmaceuticals, maker of DRP-104. Contact: Gregory Williams gregory.williams@nyulangone.org

2023-08-30

·生物制品圈

培训课程丨稳定细胞株的开发与建库：以终为始的CMC开发控制策略

课程背景01无论是抗体、重组蛋白药物的生产还是基因与细胞治疗药物的制备，都涉及单克隆细胞株的筛选。在抗体和重组蛋白药物工艺开发过程中，研发人员需要分离单细胞克隆，筛选出高产且稳定的细胞株来建立种子细胞库和工作细胞库，用于后续的抗体、重组蛋白药物的生产。创建稳定高产的生产用细胞株可以大大缩减整个CMC的周期，在保持所需质量属性的同时，还可以降低整个生产过程的成本。在CRISPR介导的基因编辑领域中，CRISPR工作流程中的一个主要瓶颈是单细胞克隆。因为基因编辑过程往往会损害细胞的生存能力，转染后得到的细胞群是异质的，具有不同程度的基因编辑，所以需要通过将编辑成功的细胞从未转染的细胞中分离富集并克隆，创建均一的单克隆细胞系，用于进一步表征，以确保正确的基因编辑。欧洲药品管理局（EMA）和美国食品药品监督管理局（FDA）要求在使用转基因细胞的医疗应用中，必须保证基因变化的安全性和可追溯性。目前，您在细胞株的开发和建库中是否有以下困恼：是否还在为转染后细胞活率低而焦虑？是否在为用有限稀释法铺几十块甚至上百块96孔板的繁重的工作量而苦恼？是否一整天守候在成像设备旁重复的拍照就是为获取单克隆证据？是否因为得不到稳定的高产的细胞株而一筹莫展？如果您有关于细胞株开发相关的困恼，欢迎来参加艾贝泰举办的关于细胞株开发与建库的培训课程。我们隆重邀请到丽珠生物总监林博士、艾迪基因盖博士分别为大家带来抗体/重组蛋白药物、基因编辑的单克隆细胞库的开发与建库：以终为始的CMC开发控制策略的培训课程，在培训课程后还有实践操作，满满的干货，让您学有所得！培训课程的意义02通过满满一天的培训课程和老师的具体案例分享，将从宏观角度了解细胞株开发过程的整体流程，也能从具体的实验细节中学习如何解决细胞株开发中遇到的难点和痛点，有助于立体的掌握如何快速开发稳定的细胞株。面向人群03与细胞株开发、建库工作相关的所有人员均可参与课程安排0401细胞株开发的现状与优化目标1.1 细胞株开发的现状与难点1.2 细胞株构建的流程与关键点控制02宿主细胞与表达载体的选择2.1 工业宿主细胞的选择与工程化改造2.2 表达载体的选择03细胞转染与筛选3.1 转染方法的选择3.2 如何提升稳转的效率及相关案例分享3.3 筛选压力的选择04单克隆筛选方法及案例分享4.1 单克隆筛选法规要求4.2 Minipool 和Bulk pool的选择与对比4.3 不同单克隆筛选方法对比4.4 单克隆筛选新技术优势及案例分享05单克隆培养基的优化5.1 培养基的选择与目标5.2 培养基的筛选与优化06单克隆细胞株的评价与案例分享6.1 单克隆细胞株的表达量、稳定性等评估6.2 单克隆细胞株的可放大生产评估07细胞库的建立与检定7.1 MCB、WCB的建立与检测7.2 细胞库的遗传稳定性研究08细胞株构建中IND和BLA的申报及注意事项8.1 申报的要求和关键点研究8.2 细胞株构建中美IND/BLA申报的差异8.3 申报注意事项和案例分享09上市后细胞株变更的相关研究与申报策略9.1 上市后细胞株变更的国内外法规和指导原则9.2 上市后细胞株变更的研究内容、工艺验证、可比性研究9.3 上市后细胞株变更的注册策略10基因编辑技术的发展历程10.1 传统的基因编辑技术10.2 从ZFNs技术到CRISPR/Cas的基因编辑技术的发展历程11基于CRISPR/CAS技术构建和筛选全基因组敲除的细胞库11.1 sgRNA文库构建与RNP递送11.2 基因编辑细胞的单克隆筛选与验证12基因编辑技术的应用及案例分享12.1 基因编辑疗法及体内治疗案例12.2 疾病诊断及新冠检测案例分享12.3 合成生物学13实操培训培训讲师介绍05毕业于韩国梨花女大，中科院深圳先进院博士后，现任丽珠生物总监。近10年研发经验，负责建立与优化高效细胞株开发平台，最快6个月获批临床。曾负责与参与各类生物制品的立项与工程细胞株开发工作，其中3项获批上市/紧急使用，多项进入IND与BLA。擅长成药性评估、工程细胞株开发与鉴定、细胞工艺开发以及完整申报工作。多年早期研发经验，曾发表SCI-11篇，专利-5件。毕业于日本北海道大学，硕士生导师。主要基于蛋白质的三维立体结构和CRISPR-CAS基因编辑技术开展基因编辑用酶、CRISPR检测和基因治疗方面的基础研发、产业应用与产业转化。盖作启博士成功解析了第一个完整血蓝蛋白的晶体结构，这也是迄今为止解析出的最大分子量的蛋白质晶体结构，其结果发表在结构生物学领域的权威杂志Structure上；盖作启博士申请的发明专利一株产谷氨酰胺酶的解淀粉芽孢杆菌及其应用有望打破日本天野公司对谷氨酰胺酶的垄断，填补国内在此领域的空白。在专业权威期刊《Structure》、《Journal of Synchrotron radiation》等权威杂志发表期刊论文16篇。主持广东省自然科学基金1项和企业开发项目，获批佛山市三水区揽月人才创业团队项目、参与国家自然科学基金面上项目1项。有丰富的产业经验和创业经验，个人和所创办的企业多次在全国创新创业大赛获奖，创业项目被评为人力资源与社会保障部优秀创业项目，荣获人力资源与社会保障部第一届全国博士后创新创业大赛创业组铜奖。培训方式06本次培训拟定于2023年9月15日在广州线下举办，具体地址报名成功后，将邮件和微信告知。上课时间：9月15日 09:00-12:00 13:30-17:00签到时间：9月15日 8:30-9:00培训课程费用07课程费用：2600元/人早鸟价：1999元/人（仅限9月8日前报名）费用包含培训材料，餐费报名方式08扫码即可报名识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。点击“阅读原文”，即可报名参与

细胞疗法基因疗法疫苗