更新于：2024-11-01

DGKζ

更新于：2024-11-01

基本信息

别名

DAG kinase zeta、DAGK5、DAGK6

+ [5]

简介

Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:9159104, PubMed:15544348, PubMed:18004883, PubMed:19744926, PubMed:22108654, PubMed:22627129, PubMed:23949095). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (PubMed:9159104, PubMed:15544348, PubMed:18004883, PubMed:19744926, PubMed:22108654, PubMed:22627129, PubMed:23949095). Also plays an important role in the biosynthesis of complex lipids (Probable). Does not exhibit an acyl chain-dependent substrate specificity among diacylglycerol species (PubMed:9159104, PubMed:19744926, PubMed:22108654). Can also phosphorylate 1-alkyl-2-acylglycerol in vitro but less efficiently and with a preference for alkylacylglycerols containing an arachidonoyl group (PubMed:15544348, PubMed:19744926, PubMed:22627129). The biological processes it is involved in include T cell activation since it negatively regulates T-cell receptor signaling which is in part mediated by diacylglycerol (By similarity). By generating phosphatidic acid, stimulates PIP5KIA activity which regulates actin polymerization (PubMed:15157668). Through the same mechanism could also positively regulate insulin-induced translocation of SLC2A4 to the cell membrane (By similarity). Regulates RASGRP1 activity. Does not regulate RASGRP1 activity.

关联

项与 DGKζ 相关的药物

BMS-986408

靶点

DGKA x DGKζ

作用机制

DGKA抑制剂 [+1]

在研机构

Bristol Myers Squibb Co.

原研机构

Bristol-Myers Squibb Pharmaceuticals Ltd.

在研适应症

晚期恶性实体瘤

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

ASP-1570

靶点

DGKζ

作用机制

DGKζ抑制剂

在研机构

Astellas Pharma Global Development, Inc. [+1]

原研机构

Astellas Pharma, Inc.

在研适应症

晚期恶性实体瘤 [+3]

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

BAY-2965501

靶点

DGKζ

作用机制

DGKζ抑制剂

在研机构

Bayer AG [+2]

原研机构

Bayer AG

在研适应症

晚期恶性实体瘤 [+1]

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 DGKζ 相关的临床试验

CTR20242146 / Recruiting临床1期

一项开放性、I 期、首次用于人体的剂量递增和剂量扩展，旨在评价二酰基甘油激酶 zeta 抑制剂（DGKzi）BAY 2965501 单药治疗和联合治疗晚期实体瘤研究参与者的安全性、耐受性、最大耐受剂量或最大给药剂量、药代动力学、药效学和肿瘤缓解情况的研究

研究人员正在寻找治疗晚期实体瘤患者的更好方法。晚期实体瘤是指可能已扩散到附近组织、淋巴结和/或身体远处部位的癌症类型，目前可用的治疗方法不太可能治愈或控制这些癌症。这项研究主要针对某些类型的皮肤癌、肾癌、胃癌和肺癌。研究治疗药物 BAY2965501 目前正在开发中，可作为单一疗法或与一种名为 pembrolizumab 的药物联合使用，用于治疗晚期实体瘤患者。BAY2965501 可阻断 T 细胞中的一种酶，从而激活 T 细胞。T 细胞是一种已知具有抗癌作用的免疫细胞，而 BAY2965501 是一种潜在的新型免疫疗法。这项首次人体试验的主要目的是了解 - 不同剂量的 BAY2965501 在单药或联合用药时的安全性如何； - BAY2965501 在单药或联合用药时引起的医疗问题的耐受程度（也称为耐受性）； - 单药或联合用药的最大用量是多少； - 单药或联合用药如何进入、通过和排出体外。中国患者暂不参与联合用药组。

开始日期2024-08-26

申办/合作机构

Bayer AG

[+2]

CTIS2023-503996-38-00 / Not yet recruiting

- BGB-A317-30813-101

开始日期2023-10-17

申办/合作机构

BeiGene Ltd.

NCT05904496 / Active, not recruiting临床1期

A Phase 1a/1b Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of the DGKζ Inhibitor BGB-30813, Alone or in Combination With the Anti-PD-1 Monoclonal Antibody Tislelizumab in Patients With Advanced or Metastatic Solid Tumors

This is a First in Human (FIH) Phase 1, multicenter, open label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of BGB-30813 as monotherapy or in combination with tislelizumab in participants with advanced or metastatic solid tumors. The study will be conducted in 2 parts: Phase 1a dose escalation and Phase 1b dose expansion.

开始日期2023-07-19

申办/合作机构

BeiGene Ltd.

100 项与 DGKζ 相关的临床结果

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100 项与 DGKζ 相关的转化医学

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0 项与 DGKζ 相关的专利（医药）

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193

项与 DGKζ 相关的文献（医药）

2024-11-01·Science China Life Sciences

Whole-genome sequencing identifies novel genes for autism in Chinese trios

Article

作者: Liu, Jia Jia ; Guo, Yanqing ; Yang, Li ; Luo, Lingxue ; Zhao, Yilu ; Lu, Lin ; Chang, Suhua ; Gao, Xuping ; Pang, Tao ; Liu, Jing ; Song, Zhirui ; Zheng, Xiangyu ; Zhang, Anyi

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (P<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (SCN2A, NF1, SHANK3, CHD8 etc.), several high confidence genes were highlighted by a series of functional analyses, including CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1, and MRPL12, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of de novo variants found in patient was significantly associated with the parents' ages at the birth of the child, and gender with trend. We also identified small de novo structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.

2024-10-01·Journal of Leukocyte Biology

Sorting nexin 27–dependent regulation of Lck and CD4 tunes the initial stages of T-cell activation

Article

作者: Rodriguez-Rodriguez, Cristina ; González-Mancha, Natalia ; Ochoa-Echeverría, Ane ; Mérida, Isabel

AbstractSorting nexin 27 is a unique member of the sorting nexin family of proteins that mediates the endosome-to-plasma membrane trafficking of cargos bearing a PSD95/Dlg1/ZO-1 (PDZ)–binding motif. In brain, sorting nexin 27 regulates synaptic plasticity, and its dysregulation contributes to cognitive impairment and neuronal degeneration. In T lymphocytes, sorting nexin 27 partners with diacylglycerol kinase ζ to facilitate polarized traffic and signaling at the immune synapse. By silencing sorting nexin 27 expression in a human T-cell line, we demonstrate that sorting nexin 27 is a key regulator of the early T-cell tyrosine-based signaling cascade. Sorting nexin 27 transcriptionally controls CD4 abundance in resting conditions and that of its associated molecule, Lck. This guarantees the adequate recruitment of Lck at the immune synapse, which is indispensable for subsequent activation of tyrosine phosphorylation-regulated events. In contrast, reduced sorting nexin 27 expression enhances NF-κB–dependent induction of CXCR4 and triggers production of lytic enzymes and proinflammatory cytokines. These results provide mechanistic explanation to previously described sorting nexin 27 function in the control of immune synapse organization and indicate that impaired sorting nexin 27 expression contributes to CD4 T-cell dysfunction.

2024-10-01·Advances in Biological Regulation

Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways

Article

作者: Murakami, Chiaki ; Sakai, Hiromichi ; Sakane, Fumio

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprise ten isozymes (α-κ) that regulate a wide variety of physiological and pathological events. Recently, we revealed that DGK isozymes use saturated fatty acid (SFA)/monosaturated fatty acid (MUFA)-containing and docosahexaenoic acid (22:6)-containing DG species, but not phosphatidylinositol (PI) turnover-derived 18:0/20:4-DG. For example, DGKδ, which is involved in the pathogenesis of type 2 diabetes, preferentially uses SFA/MUFA-containing DG species, such as 16:0/16:0- and 16:0/18:1-DG species, in high glucose-stimulated skeletal muscle cells. Moreover, DGKδ, which destabilizes the serotonin transporter (SERT) and regulates the serotonergic system in the brain, primarily generates 18:0/22:6-PA. Furthermore, 16:0/16:0-PA is produced by DGKζ in Neuro-2a cells during neuronal differentiation. We searched for SFA/MUFA-PA- and 18:0/22:6-PA-selective binding proteins (candidate downstream targets of DGKδ) and found that SFA/MUFA-PA binds to and activates the creatine kinase muscle type, an energy-metabolizing enzyme, and that 18:0/22:6-PA interacts with and activates Praja-1, an E3 ubiquitin ligase acting on SERT, and synaptojanin-1, a key player in the synaptic vesicle cycle. Next, we searched for SFA/MUFA-DG-generating enzymes upstream of DGKδ. We found that sphingomyelin synthase (SMS)1, SMS2, and SMS-related protein (SMSr) commonly act as phosphatidylcholine (PC)-phospholipase C (PLC) and phosphatidylethanolamine (PE)-PLC, generating SFA/MUFA-DG species, in addition to SMS and ceramide phosphoethanolamine synthase. Moreover, the orphan phosphatase PHOSPHO1 showed PC- and PE-PLC activities that produced SFA/MUFA-DG. Although PC- and PE-PLC activities were first described 70-35 years ago, their proteins and genes were not identified for a long time. We found that DGKδ interacts with SMSr and PHOSPHO1, and that DGKζ binds to SMS1 and SMSr. Taken together, these results strongly suggest that there are previously unrecognized signal transduction pathways that include DGK isozymes and generate and utilize SFA/MUFA-DG/PA or 18:0/22:6-DG/PA but not PI-turnover-derived 18:0/20:4-DG/PA.

项与 DGKζ 相关的新闻（医药）

2024-06-27

·echemi

Bayer's Novel Drugs for Late-Stage Solid Tumors and Acute Ischemic Stroke Receive Clinical Trial Approvals in China

According to the recent announcement on the CDE (China's Center for Drug Evaluation) website, Bayer has successfully obtained clinical trial approvals for two of its novel Class 1 drugs, which are aimed at addressing the treatment needs of patients with late-stage solid tumors and acute ischemic stroke. Based on Bayer's public information, one of the new drugs is a DGKα inhibitor, and the other is a protein-based drug targeting α2AP. These two candidates are currently in Phase 1 and Phase 2 clinical development stages, respectively, at the international level. BAY 2862789 oral solution, a small-molecule DGKα inhibitor co-developed by Bayer and the German Cancer Research Center (DKFZ), is now undergoing the first-in-human Phase 1 clinical trial globally. Its research and development target is the treatment of solid tumors. The diacylglycerol kinase (DGK) family plays a crucial role in the development, differentiation, and functional regulation of T cells and NK cells, with DGKα and DGKζ being the predominant isoforms. Studies have shown that DGKα is significantly expressed in various refractory cancers, promoting cell proliferation and inhibiting apoptosis. Its high expression is closely related to T-cell exhaustion, which is a key factor in the evasion of immune surveillance by late-stage cancers. Therefore, the specific inhibition of DGKα holds great potential in the field of cancer therapy, as it can effectively suppress cancer cell proliferation and activate T-cell functions, achieving a dual anti-cancer effect. Furthermore, the synergistic effect of this inhibitor with PD-1/PD-L1 inhibitors offers new hope for the treatment of refractory cancers. The other new drug, BAY 3018250, is a protein-based drug targeting α2AP, which is part of Bayer's cardiovascular disease research and development pipeline. It aims to treat acute ischemic stroke and pulmonary embolism. Currently, this drug has made significant progress in the international Phase 2 clinical trial for the treatment of deep vein thrombosis (DVT). DVT is a serious health issue that can lead to life-threatening blockage of blood flow in the lungs. BAY 3018250 exerts its therapeutic effect by dissolving blood clots. Thrombotic vascular occlusion is a key factor in the development of ischemic stroke, and α2-antiplasmin (α2AP), a member of the serine protease inhibitor family, is closely associated with an increased risk of ischemic stroke and the failure of recombinant tissue plasminogen activator (rt-PA) treatment. Research has shown that anti-α2AP therapy can significantly reduce the formation of microvascular thrombosis, ischemic brain injury, brain edema, intracerebral hemorrhage, and mortality after ischemic stroke, suggesting that the temporary inactivation of α2AP may have potential therapeutic value for ischemic stroke. With the approval for clinical trials in China, BAY 3018250 will now be evaluated for the specific indication of acute ischemic stroke, bringing new hope for the treatment of this condition.

临床1期临床2期

2024-06-21

·医药观澜

拜耳2款新药在中国获批临床，治疗癌症、脑卒中！

中国国家药监局药品审评中心（CDE）官网公示，近日拜耳（Bayer）公司申报的两款1类新药获得临床试验默示许可，分别拟用于治疗晚期实体瘤和急性缺血性脑卒中患者。根据拜耳公开资料，这两款新药分别为DGKα抑制剂和抗a2AP的蛋白质药物，在国际上分别处于1期和2期临床阶段。 BAY 2862789口服溶液：DGKα抑制剂适应症：晚期实体瘤 BAY 2862789口服溶液由拜耳与德国癌症研究中心（DKFZ）合作开发，为小分子DGKα抑制剂，目前在国际范围内处于1期首次人体研究阶段，拟开发治疗实体瘤。甘油二酯激酶（DGKs）家族被认为是T细胞和NK细胞发育、分化和功能的生理调节剂，在多种细胞信号传导通路中起着重要的调节作用。DGKα和DGKζ均是DGKs主要的亚型，二者在T细胞中的上调均会导致T细胞沉默。研究表明，DGKα在几种难治性肿瘤细胞中高表达，包括黑色素瘤、肝细胞癌、胶质母细胞瘤等，它能减缓细胞凋亡、促进细胞增殖。除癌细胞外，DGKα在T细胞中也非常丰富，并诱导T细胞沉默，这是晚期癌症逃过免疫作用的主要机制。因此，DGKα特异性抑制剂治疗癌症有望发挥抑制癌细胞增殖、同时激活T细胞功能的双重抗癌作用。此外，抑制DGKα可协同增强PD-1/L1的抗癌作用，为难治性癌症提供了一种有希望的新治疗策略。值得一提的是，拜耳与德国癌症研究中心（DKFZ）还合作开发了一款DGKζ抑制剂BAY 2965501，该产品已经于今年4月在中国获批临床。研究表明，联合抑制/沉默DGKα和DGKζ可协同刺激黑色素瘤细胞凋亡和T细胞中白细胞介素-2的产生，二者有望产生协同抗癌作用。 BAY 3018250：抗a2AP的蛋白质药物适应症：急性缺血性脑卒中血栓性血管闭塞是缺血性卒中的主要原因。α2-抗纤溶酶（a2AP）是一种纤溶酶抑制剂，为丝氨酸蛋白酶抑制剂家族的一员，与缺血性卒中、组织纤溶酶原激活剂（rt-PA）治疗失败的风险增加有关。抗a2AP治疗可显著减少血栓栓塞性卒中后微血管血栓形成、缺血性脑损伤、脑肿胀、脑出血和死亡，这些研究提示暂时失活a2AP可能对缺血性脑卒中具有治疗价值。 BAY 3018250是拜耳心血管疾病研发管线中的一员，为抗a2AP的蛋白质类药物，拟开发治疗急性缺血性卒中和肺栓塞。该产品在国际范围内目前正处于治疗深静脉血栓（DVT）的2期临床研究阶段。DVT会导致严重的健康问题，包括血凝块卡在肺部，阻碍血液流向肺部等。BAY3018250可以通过溶解血凝块起到治疗作用。本次BAY 3018250在中国获批临床，针对适应症为急性缺血性脑卒中。这意味着该产品即将在中国开展针对这种新适应症的临床研究。参考资料： [1]中国国家药监局药品审评中心（CDE）官网. Retrieved June 20，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]拜耳研发管线. . Retrieved Apr 30，2024, From https://www.bayer.com/sites/default/files/ph-rd-pipeline-2024-05-final-1.pdf [3]Sakane F, et al. (2021)The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis. Cancers (Basel). doi: 10.3390/cancers13205190. [4]Reed GL, Houng AK, Singh S, Wang D. （2017）α2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke. Semin Thromb Hemost. doi: 10.1055/s-0036-1585077. 内容来源于网络，如有侵权，请联系删除。

ASH会议细胞疗法申请上市临床申请

2024-02-07

·医药观澜

新型肿瘤免疫疗法！拜耳DGKζ抑制剂在中国申报临床

2月6日，中国国家药监局药品审评中心（CDE）官网公示，拜耳（Bayer）公司申报了BAY 2965501片的临床试验申请并获得受理。公开资料显示，这是一款新型肿瘤免疫疗法，为一款DGKζ抑制剂。公开资料显示，DGKζ是磷酸二酰甘油激酶家族的一员，其对多种细胞信号传导通路起着重要的调节作用。研究发现，DGKζ在多种肿瘤中的表达水平增高，与肿瘤的发病、发展和预后相关，因此DGKζ被认为是一个新的肿瘤免疫治疗靶点。据文献报道，DGKζ抑制剂通过阻断DGKζ的活性，从而阻止肿瘤细胞的增殖和存活。具体来说，DGKζ可以催化生物膜上的二酰基甘油（DAG）转化为磷脂酸来下调T细胞的活化，从而作为一个不依赖配体的细胞内免疫检查点。抑制DGKζ已被证明可以增强T细胞对次优肿瘤抗原的启动，并以TCR参与依赖的方式克服肿瘤微环境中的多种免疫抑制机制。根据拜耳公开资料，BAY 2965501由拜耳公司与德国癌症研究中心（DKFZ）合作开发，为一种高选择性的口服DGKζ抑制剂。在临床前研究中，该化合物可以增加自然杀伤细胞和T细胞介导的肿瘤细胞杀伤，增强白细胞介素2诱导的自然杀伤细胞活化，且能够克服T细胞中转化生长因子β、前列腺素E2和腺苷信号传递的抑制信号。体外研究还表明，与抗PD-1抗体单药相比，BAY 2965501联合抗PD-1抗体可降低肿瘤生长速度。临床前毒理学研究显示该产品只有低级别的胃肠道效应，表明临床可耐受。这项临床前研究数据此前已经在2023年美国癌症研究协会（AACR）年会上发表。根据ClinicalTrials官网，拜耳于2024年初刚刚在美国、日本等地启动BAY 2965501的首次人体1期临床研究，评估该药单药或与抗PD-1单抗联用治疗晚期实体瘤的安全性、耐受性和初步有效性等。这项研究的重点是某些类型的皮肤癌、肾癌、胃癌和肺癌。参考资料： [1]中国国家药监局药品审评中心（CDE）官网.Retrieved Feb 6，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]Bayer to present latest research across its advancing oncology portfolio at AACR 2023 Annual Meeting .Retrieved Apr 11 , 2023, From https://www.bayer.com/media/en-us/bayer-to-present-latest-research-across-its-advancing-oncology-portfolio-at-aacr-2023-annual-meeting/ 内容来源于网络，如有侵权，请联系删除。