更新于：2024-11-01

SGK1

更新于：2024-11-01

基本信息

别名

Serine/threonine-protein kinase Sgk1、serum/glucocorticoid regulated kinase、serum/glucocorticoid regulated kinase 1

+ [3]

简介

Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis. Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis. Sustained high levels and activity may contribute to conditions such as hypertension and diabetic nephropathy. Isoform 2 exhibited a greater effect on cell plasma membrane expression of SCNN1A/ENAC and Na(+) transport than isoform 1.

关联

项与 SGK1 相关的药物

LQT-1213

靶点

SGK1

作用机制

SGK1 inhibitors

在研机构

Thryv Therapeutics, Inc.初创企业

原研机构

Thryv Therapeutics, Inc.初创企业

在研适应症

QT间期延长综合征2 [+2]

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

LQT-1268

靶点

SGK1

作用机制

SGK1 inhibitors

在研机构

Thryv Therapeutics, Inc.初创企业

原研机构

Thryv Therapeutics, Inc.初创企业

在研适应症

心房颤动 [+2]

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

THRYV-1257

靶点

SGK1

作用机制

SGK1 inhibitors

在研机构

Thryv Therapeutics, Inc.初创企业

原研机构

Thryv Therapeutics, Inc.初创企业

在研适应症

甲状腺未分化癌 [+2]

非在研适应症

乳腺癌 [+3]

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 SGK1 相关的临床试验

NCT06507839 / Recruiting临床1期

A First-in-Human, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study To Assess the Safety, Tolerability, Pharmacokinetics, and Food Effect of Thrv-1268 in Healthy Adult Subjects

This is a single-center, randomized, double-blind, placebo-controlled study to be conducted in 2 parts: single ascending dose (SAD) incorporating a food effect arm and multiple ascending dose (MAD). Potential participants for each part will undergo screening procedures within 28 days of enrollment.

开始日期2024-06-06

申办/合作机构

Thryv Therapeutics, Inc.初创企业

NCT05906732 / Recruiting临床1/2期

A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed With Type 1, 2 or 3 Long QT Syndrome

Part 1: This is a Phase 1b, randomized, double-blind, crossover, dose escalation, placebo-controlled study to evaluate the effect of oral LQT-1213 on dofetilide-induced QTc prolongation in healthy adult subjects. This is a 2-treatment, 2-period crossover study with approximately up to 28 healthy subjects, with screening procedures within 28 days of enrolment.
Part 2: This is a Phase 2a, single-blind, placebo run-in, multiple-dose safety study to evaluate the safety, tolerability, and PK of LQT-1213 in patients diagnosed with LQT1, LQT2 or LQT3. Up to 12 participants with LQT1, up to 20 participants with LQT2 and up to 12 participants with LQT3 will be recruited.

开始日期2023-03-12

申办/合作机构

Thryv Therapeutics, Inc.初创企业

NCT05759962 / Completed临床1期

A Phase 1, Randomized, Double-blinded, Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluated the Safety, Tolerability, Pharmacokinetics, Food Effect, and Pharmacodynamics of LQT-1213 in Healthy Adult Participants

开始日期2022-09-14

申办/合作机构

Thryv Therapeutics, Inc.初创企业

100 项与 SGK1 相关的临床结果

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100 项与 SGK1 相关的转化医学

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0 项与 SGK1 相关的专利（医药）

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1,505

项与 SGK1 相关的文献（医药）

2024-12-01·Molecular Biology Reports

The role of serum-glucocorticoid regulated kinase 1 in reproductive viability: implications from prenatal programming and senescence

Review

作者: Fu, Zhujing ; Zhou, Xuanle ; Tian, Ye ; Wu, Shuangyu ; Lou, Yiyun ; Shen, Wendi ; Lan, Huizhen ; Zhang, Qiying

AbstractObjectiveOrganisms and cellular viability are of paramount importance to living creatures. Disruption of the balance between cell survival and apoptosis results in compromised viability and even carcinogenesis. One molecule involved in keeping this homeostasis is serum-glucocorticoid regulated kinase (SGK) 1. Emerging evidence points to a significant role of SGK1 in cell growth and survival, cell metabolism, reproduction, and life span, particularly in prenatal programming and reproductive senescence by the same token. Whether the hormone inducible SGK1 kinase is a major driver in the pathophysiological processes of prenatal programming and reproductive senescence?MethodThe PubMed/Medline, Web of Science, Embase/Ovid, and Elsevier Science Direct literature databases were searched for articles in English focusing on SGK1 published up to July 2023ResultEmerging evidence is accumulating pointing to a pathophysiological role of the ubiquitously expressed SGK1 in the cellular and organismal viability. Under the regulation of specific hormones, extracellular stimuli, and various signals, SGK1 is involved in several biological processes relevant to viability, including cell proliferation and survival, cell migration and differentiation. In line, SGK1 contributes to the development of germ cells, embryos, and fetuses, whereas SGK1 inhibition leads to abnormal gametogenesis, embryo loss, and truncated reproductive lifespan.ConclutionSGK1 integrates a broad spectrum of effects to maintain the homeostasis of cell survival and apoptosis, conferring viability to multiple cell types as well as both simple and complex organisms, and thus ensuring appropriate prenatal development and reproductive lifespan.

2024-12-01·Nano-Micro Letters

Highly Aligned Ternary Nanofiber Matrices Loaded with MXene Expedite Regeneration of Volumetric Muscle Loss

Article

作者: Hong, Suck Won ; Kang, Moon Sung ; Heo, Hye Jin ; Yu, Yeuni ; Han, Dong-Wook ; Kim, Yun Hak ; Park, Rowoon ; Lee, Seok Hyun

AbstractCurrent therapeutic approaches for volumetric muscle loss (VML) face challenges due to limited graft availability and insufficient bioactivities. To overcome these limitations, tissue-engineered scaffolds have emerged as a promising alternative. In this study, we developed aligned ternary nanofibrous matrices comprised of poly(lactide-co-ε-caprolactone) integrated with collagen and Ti3C2Tx MXene nanoparticles (NPs) (PCM matrices), and explored their myogenic potential for skeletal muscle tissue regeneration. The PCM matrices demonstrated favorable physicochemical properties, including structural uniformity, alignment, microporosity, and hydrophilicity. In vitro assays revealed that the PCM matrices promoted cellular behaviors and myogenic differentiation of C2C12 myoblasts. Moreover, in vivo experiments demonstrated enhanced muscle remodeling and recovery in mice treated with PCM matrices following VML injury. Mechanistic insights from next-generation sequencing revealed that MXene NPs facilitated protein and ion availability within PCM matrices, leading to elevated intracellular Ca2+ levels in myoblasts through the activation of inducible nitric oxide synthase (iNOS) and serum/glucocorticoid regulated kinase 1 (SGK1), ultimately promoting myogenic differentiation via the mTOR-AKT pathway. Additionally, upregulated iNOS and increased NO– contributed to myoblast proliferation and fiber fusion, thereby facilitating overall myoblast maturation. These findings underscore the potential of MXene NPs loaded within highly aligned matrices as therapeutic agents to promote skeletal muscle tissue recovery.

2024-12-01·Cellular and Molecular Life Sciences

Novel role of NCoR1 in impairing spatial memory through the mediation of a novel interacting protein DEC2

Article

作者: Lee, Eminy H Y ; Hsu, Wei-Lun ; Liu, Yen-Chen ; Cheng, Kuang-Min ; Ma, Yun-Li

AbstractLong-term memory formation requires de novo RNA and protein synthesis. Using differential display PCR, we found that the NCoR1 cDNA fragment is differentially expressed between fast learners and slow learners, with fast learners showing a lower expression level than slow learners in the water maze learning task. Fast learners also show lower NCoR1 mRNA and protein expression levels. In addition, spatial training decreases both NCoR1 mRNA and protein expression, whereas NCoR1 conditional knockout (cKO) mice show enhanced spatial memory. In studying the molecular mechanism, we found that spatial training decreases the association between NCoR1 and DEC2. Both NCoR1 and DEC2 suppress the expression of BDNF, integrin α3 and SGK1 through C/EBPα binding to their DNA promoters, but overexpression of DEC2 in NCoR1 cKO mice rescues the decreased expression of these proteins compared with NCoR1 loxP mice overexpressing DEC2. Further, spatial training decreases DEC2 expression. Spatial training also enhances C/EBPα binding to Bdnf, Itga3 and Sgk1 promoters, an effect also observed in fast learners, and both NCoR1 and DEC2 control C/EBPα activity. Whereas knockdown of BDNF, integrin α3 or SGK1 expression impairs spatial learning and memory, it does not affect Y-maze performance, suggesting that BDNF, integrin α3 and SGK1 are involved in long-term memory formation, but not short-term memory formation. Moreover, NCoR1 expression is regulated by the JNK/c-Jun signaling pathway. Collectively, our findings identify DEC2 as a novel interacting protein of NCoR1 and elucidate the novel roles and mechanisms of NCoR1 and DEC2 in negative regulation of spatial memory formation.

项与 SGK1 相关的新闻（医药）

2024-10-01

·PRNewswire

Thryv Therapeutics Granted FDA Orphan Drug Designation for LQT-1213 in Long QT Syndrome Treatment

MONTREAL, Oct. 1, 2024 /PRNewswire/ - Thryv Therapeutics, a clinical stage biotech company dedicated to developing treatments for rare and life-threatening cardiovascular indications, today announced that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to LQT-1213 for the treatment of Long QT Syndrome (LQTS). LQT-1213 is a novel, first-in-class SGK1 inhibitor specifically designed to treat congenital LQTS. Thryv has developed a series of SGK1 inhibitors for the treatment of cardiometabolic stress associated with various arrhythmic diseases including LQTS, atrial fibrillation, and heart failure. "We are pleased with the FDA's Orphan Drug Designation for LQT-1213 based partly on emerging positive clinical data from our Wave 1 clinical study in patients with Long QT Syndrome" said Debra Odink, PhD, President and Chief Development Officer of Thryv Therapeutics. "People with Long QT Syndrome deserve a properly studied and FDA-approved therapy to help in their battle against this potentially lethal genetic disease. There is currently no FDA-approved therapy for people with Long QT Syndrome. This designation reinforces the potential of LQT-1213 to fulfill this unmet need and provides critical incentives for Thryv to accelerate our efforts to deploy prospectively designed, pivotal efficacy studies in people with congenital Long QT Syndrome. We remain focused on bringing innovative treatments to adults and children with rare diseases who have limited options." Following a request from the FDA, clinical data from the ongoing Wave I clinical study in people with congenital LQTS was provided to the Office of Orphan Products Designation. Shortly thereafter, the company received notification that its request for Orphan Drug Designation was approved. The FDA Orphan Drug Designation is a special status granted to drugs and biologics targeting rare diseases, defined as those affecting fewer than 200,000 people in the United States. This designation offers numerous benefits to support the development of treatments for rare conditions, including tax credits for clinical trial costs, exemption from certain FDA fees, and up to seven years of market exclusivity following FDA approval. About LQT-1213 LQT-1213 is a potent and selective serum glucocorticoid regulated kinase 1 (SGK1) inhibitor being developed as an investigational therapeutic to treat Long QT Syndrome Type 1, 2, and 3. By targeting SGK1, LQT-1213 aims to reduce the prolonged QTc interval in people with LQTS, thereby decreasing the risk of life-threatening arrhythmias. Currently, LQT-1213 is being evaluated in clinical studies for its efficacy and safety in treating congenital LQTS. Additional information about the on-going Wave I clinical study is available at using identifier: NCT05906732. About Thryv Therapeutics Inc. Thryv Therapeutics Inc. is a privately owned company based in Montreal, Quebec, Canada. Thryv Therapeutics is pioneering a precision medicine approach to develop highly selective SGK1 inhibitors to treat Long QT Syndrome, atrial fibrillation and heart failure, with potent and selective inhibitors of Serum Glucocorticoid inducible Kinase. For more information, please visit . SOURCE Thryv Therapeutics Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

孤儿药临床1期

2024-05-16

·药渡

世界高血压日特辑 | 高血压与免疫系统

高血压是以血压升高为主要特点的全身性疾病。我国18岁及以上居民高血压患病率为 27.5%，其中 18～44 岁、45～59 岁和 60 岁及以上居民高血压患病率分别为 13.3%、37.8%和 59.2%。我国居民高血压患病率总体呈上升趋势，目前成人高血压患病人数估计为 2.45 亿。高血压是导致冠心病、脑卒中等心血管疾病、死亡的主要原因之一。（成人高血压食养指南（2023 年版）国家卫生健康委办公厅）。天然免疫系统天然免疫系统由粘膜屏障、多种免疫细胞（巨噬细胞、中性粒细胞、NK细胞等）和免疫分子（包括趋化因子、细胞因子和补体蛋白）组成，其中中性粒细胞是循环中最丰富的白细胞类型，而巨噬细胞是各种组织中最常见的免疫细胞类型。巨噬细胞Pflugers Arch. 2017巨噬细胞通过产生炎症细胞因子和活性氧（ROS），直接损害血管内皮细胞和平滑肌功能，导致血管收缩，导致高血压。肾血管中类似的过程损害肾脏钠排泄也导致血压升高。巨噬细胞诱导的肾实质损伤也可引起高血压中可见的肾小管损伤和间质纤维化。在大脑中，不同的巨噬细胞群增加了高血压神经炎症和交感神经元的激活。大脑中巨噬细胞的数量也介导了与高血压相关的神经血管功能障碍和认知功能下降。通过不同的机制，巨噬细胞增加VEGF-C的表达，导致淋巴管生成和淋巴流量增加。这些过程可以调动皮肤的钠储存，从而可能作为一个重要的肾外调节钠稳态，从而调节血压。中性粒细胞Int J Mol Sci. 2020在动脉高血压（arterial hypertension，AH），激活的中性粒细胞分泌IL-1β、IL-8等，内皮细胞分泌endothelin-1 (ET-1)，增加循环中性粒细胞（中性粒细胞总数或中性粒细胞/淋巴细胞比率（NLR））。IL-8可诱导中性粒细胞中的肾上腺素能受体表达，促进其激活。ET-1会增加粘附分子的表达，有利于内皮细胞-中性粒细胞的相互作用和粘附过程。同样，中性粒细胞分泌的S100a8/a9可能诱导内皮细胞粘附分子表达。活性氧（ROS）促进中性粒细胞粘附和滚动过程，而内皮细胞产生的一氧化氮（NO）抑制中性粒细胞粘附和滚动。循环中性粒细胞和浸润组织的中性粒细胞，通过NADPH氧化酶、髓过氧化物酶（MPO）作用，产生活性氧（ROS）和活性氮（RNS）。这种氧化和氮化应激可能导致内皮损伤，导致血管功能障碍和AH。另一方面，中性粒细胞通过分泌细胞因子、趋化因子、中性粒细胞明胶酶相关脂钙蛋白（NGAL）或S100a8/a9，促进组织损伤和免疫细胞募集，如巨噬细胞和树突状细胞。反过来，这些分子可能诱导对血液中性粒细胞的自分泌效应，促进它们的激活，以及对浸润的组织，促进重塑过程，使AH永久化。树突状细胞Hypertension Research (2022)高血压患者，树突状细胞失衡，pDC下降，mDC上调，进而引起T细胞亚群失调，Treg下调，Th17上调，参与T细胞介导的高血压。于嗜酸性粒细胞和嗜碱性粒细胞在高血压发病机制中作用的数据有限。适应性免疫系统KIDNEY360 2023T细胞通过NKCC1摄取氯化钠来响应氯化钠的增加，NKCC1被感知为SGK1。SGK1促进促炎信号通路，抑制炎症通路。ROCK2磷酸化STAT3，并降低STAT5的磷酸化，这也使细胞向炎症表型转变。炎症性Th1、Th2，特别是Th17细胞利用糖酵解产生能量。这是由细胞表面Glut1的表达和mTORC活性调控的。mTORC信号通路涉及HIF1a，一种促进Th17分化的转录因子。SH2B3作为STAT4信号通路的负调控因子，从而为炎症激活提供了一个刹车。通过操纵这些途径来调节炎症平衡，可以影响T细胞产生的细胞因子的类型，从而影响对靶器官的损伤。在高血压患者中，B细胞及其抗体在终末器官损伤中发挥作用。高血压反应被T调节细胞（Treg）及其抗炎细胞因子IL-10可以抑制高血压的发生。点击下方“药渡“，关注更多精彩内容免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

AHA会议临床结果细胞疗法

2024-05-07

·PRNewswire

Thryv Therapeutics to Present Preclinical Data of SGK1 Inhibition in Models of Drug-Induced QT Prolongation at the 2024 Heart Rhythm Society Meeting

MONTREAL, May 7, 2024 /PRNewswire/ - Thryv Therapeutics Inc., a biotechnology company pioneering precision treatment to treat indications including Congenital Long QT Syndrome, atrial fibrillation, and heart failure, today announced a poster presentation of SGK1 inhibition in models of Drug-Induced QT prolongation at the 2024 Heart Rhythm Society meeting in Boston, MA. This presentation will take place on Friday, May 17th, from 10:30 a.m. to 12:30 p.m. ET. The meeting will commence with a presentation by Thryv co-founder and Principal Scientific Advisor, Dr. Saumya Das, at the Stanford Biodesign New Arrhythmia Technologies Retreat in Boston, where he will discuss Small Molecules for Arrhythmia Therapy. Heart Rhythm 2024 Poster Presentation Title: Attenuation of Drug-Induced QT Prolongation in Guinea Pig Isolated Heart and Anesthetized Dog Models by serum/glucocorticoid-regulated kinase 1 (SGK-1) Inhibitors. Date and Time: Friday, May 17th from 10:30 a.m. to 12:30 p.m. ET. 2024 Stanford BioDesign Arrhythmia Technologies Retreat Presentation Title: Small Molecules for Arrhythmia Therapy Presenter: Saumya Das, MD, PhD Date and Time: Wednesday, May 15th at 9:04 a.m. About Thryv Therapeutics Inc. Thryv Therapeutics Inc. is a privately owned company based in Montreal, Quebec, Canada. Thryv Therapeutics is pioneering a precision medicine approach to treat indications including Congenital Long QT Syndromes (LQTS), atrial fibrillation and heart failure, with potent and selective inhibitors of Serum Glucocorticoid inducible Kinase (SGK1). For more information, please visit . SOURCE Thryv Therapeutics Inc.