更新于：2024-05-01

SGK1

serum/glucocorticoid regulated kinase 1

更新于：2024-05-01

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

长QT综合征

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

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 [+5]

非在研适应症

前列腺癌

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

RJ8201

靶点

SGK1

作用机制

SGK1 inhibitors

在研机构

南京瑞捷医药科技有限公司

原研机构

南京瑞捷医药科技有限公司

在研适应症

银屑病

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

项与 SGK1 相关的临床试验

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 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 LQT2 or LQT3. Up to 12 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

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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1,474

项与 SGK1 相关的文献（医药）

2024-02-15·Nucleosides, nucleotides & nucleic acids

Evaluation and normalization of a set of reliable reference genes for quantitative sgk-1 gene expression analysis in Caenorhabditis elegans-focused cancer research.

Article

作者: Özgür Ülkü Özdemir ; Kübra Yurt ; Ayşe Nur Pektaş ; Şeyda Berk

Multiple signaling pathways have been discovered to play a role in aging and longevity, including the insulin/IGF-1 signaling system, AMPK pathway, TOR signaling, JNK pathway, and germline signaling. Mammalian serum and glucocorticoid-inducible kinase 1 (sgk-1), which has been associated with various disorders including hypertension, obesity, and tumor growth, limits survival in C. elegans by reducing DAF-16/FoxO activity while suppressing FoxO3 activity in human cell culture. C. elegans provides significant protection for a number of genes associated with human cancer. The best known of these are the lin-35/pRb (mammalian ortholog pRb) and CEP-1 (mammalian ortholog p53) genes. Therefore, in this study, we aimed to investigate the expression analyzes of sgk-1, which is overexpressed in many types of mammalian cancer, in mutant lin-35 and to demonstrate the validation of reference genes in wild-type N2 and mutant lin-35 for C. elegans-focused cancer research. To develop functional genomic studies in C. elegans, we evaluated the expression stability of five candidate reference genes (act-1, ama-1, cdc-42, pmp-3, iscu-1) by quantitative real-time PCR using five algorithms (geNorm, NormFinder, Delta Ct method, BestKeeper, RefFinder) in N2 and lin-35 worms. According to our findings, act-1 and cdc-42 were effective in accurately normalizing the levels of gene expression in N2 and lin-35. act-1 and cdc-42 also displayed the most consistent expression patterns, therefore they were utilized to standardize expression level of sgk-1. Furthermore, our results clearly showed that sgk-1 was upregulated in lin-35 worms compared to N2 worms. Our results highlight the importance of definitive validation using mostly expressed reference genes.

2024-02-12·Biochemical pharmacology

Dexamethasone upregulates macrophage PIEZO1 via SGK1, suppressing inflammation and increasing ROS and apoptosis.

Article

作者: Hailin Liu ; Lian Zhou ; Xifeng Wang ; Qingcui Zheng ; Fenfang Zhan ; Lanqian Zhou ; Yao Dong ; Yanhong Xiong ; Pengcheng Yi ; Guohai Xu ; Fuzhou Hua

The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca²⁺ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca²⁺ influx and cytoskeletal remodelling. The increase in intracellular Ca²⁺ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca²⁺ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.

2024-02-07·Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

Manganese induces neuronal apoptosis by activating mTOR signaling pathway in vitro and in vivo.

Article

作者: Yuyan Cen ; Jianmin Yang ; Liyu Su ; Feng Wang ; Deyu Zhu ; Lan Zhao ; Yan Li

Manganese (Mn) is a well-known environmental pollutant and occupational toxicant that causes neurotoxicity, which present as neurodegenerative-like symptoms. However, the mechanism of Mn-induced neuronal injury remains unclear. In this research, we explored the mechanism of Mn-induced neurotoxicity, focusing on the mTOR signaling pathway. A plasmid expressing a short hairpin RNA (shRNA) targeting mTOR (shRNA-mTOR) was transfected into N27 cells in vitro, and rapamycin was used as an mTOR inhibitor in vivo to block the mTOR signaling pathway. Cells were treated with different concentrations of manganese (II) chloride (MnCl₂). We found that Mn induced cell injury and apoptosis and markedly upregulated the expression of mTOR pathway-related proteins. The phosphorylation of 4E-BP1, S6K1, Akt and SGK1 was markedly decreased after blocking mTOR, and cell apoptosis was also reduced. Furthermore, the mTOR-specific inhibitor rapamycin restored learning and memory abilities in vivo. This research highlights that inhibiting mTOR might be useful for preventing Mn-induced neurodegenerative-like disorders.

项与 SGK1 相关的新闻（医药）

2024-03-30

·今日头条

【STTT】广州医科大学钟南山团队最新发文

本文为转化医学网原创，转载请注明出处作者：Jerry 导读： SARS-CoV-2感染破坏上皮屏障并引发气道炎症。冠状病毒的核心毒力结构成分包膜(E)蛋白可能在这一过程中发挥作用。 2024年3月25日，广州医科大学钟南山团队在《Signal Transduction and Targeted Therapy》在线发表题为”SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl− concentration“的研究论文，该研究证明了E蛋白下调紧密连接蛋白的表达，导致气道上皮屏障的破坏。 https://www.nature.com/articles/s41392-024-01753-z 研究背景 01 SARS-CoV-2是导致COVID-19大流行的病原体，对全球公共卫生构成了重大挑战。SARS-CoV-2可能破坏肺泡上皮屏障，引发气道炎症加剧，导致呼吸困难，严重时进展为急性呼吸衰竭。然而，上皮屏障功能破坏和炎症增强的确切分子机制尚不完全清楚。了解SARS-CoV-2的致病机制有助于确定临床干预的新靶点。SARS-CoV-2是一种包膜病毒，具有正义单链RNA基因组。该病毒可破坏上皮细胞的完整性，加剧呼吸道上皮细胞的炎症，这是抵御病毒感染的第一道防线。 SARS-CoV-2编码四种结构蛋白——刺突蛋白(S)、包膜蛋白(E)、膜蛋白(M)和核衣壳蛋白(N)。S蛋白介导病毒与宿主受体血管紧张素转换酶2 (ACE2)的结合和病毒与细胞膜的融合。M蛋白在病毒组装中起着至关重要的作用，而N蛋白对病毒基因组的包装和存活至关重要。值得注意的是，E蛋白是一种核心结构毒力因子，在维持病毒生命周期(如病毒组装)中起着至关重要的作用。一些研究探索了SARS-CoV-2 S、M和N蛋白的致病作用。然而，SARS-CoV-2 E蛋白在上皮紧密连接和粘膜炎症中的作用和机制尚不清楚。研究进展 02 鉴于E蛋白以PDE4-cAMP依赖的方式增加[Cl−]i，研究人员研究了靶向PDE4的药物对E蛋白介导的[Cl−]i升高和气道炎症的潜在保护作用。罗利普兰，一种选择性PDE4抑制剂，消除了E蛋白在人气道上皮细胞和mPAECs中引起的[Cl−]i升高。此外，罗利普兰治疗减轻了气道上皮细胞中IκB的磷酸化和促炎性细胞因子/趋化因子的上调。重要的是，在SARS-CoV-2 E蛋白刺激的小鼠气管内灌注模型中，罗利普兰抑制了mPAECs中升高的[Cl−]i，并在肺组织中发挥抗炎作用。这些结果表明，针对PDE4抑制的药理学干预可能有效地减轻气道上皮细胞内的细胞内Cl−积累，并减轻SARS-CoV-2感染引起的气道炎症。为了验证上述发现，研究人员最终采用了hPAECs模型。有趣的是，E蛋白下调了hPAECs中ZO-1和闭合蛋白的表达，而claudin-4的表达则不受影响。此外，E蛋白引发了过度的炎症反应，其特征是促炎细胞因子的表达增加，以及hPAECs中JNK、IκB和SGK1的磷酸化水平升高。与在人气道上皮细胞系中的观察结果一致，E蛋白没有改变CFTR的表达，而是增加了PDE4亚型的表达，导致hPAECs中Cl−的异常积累。这些结果进一步证实了SARS-CoV-2 E蛋白在破坏气道上皮完整性、促进炎症反应和扰乱气道上皮细胞内Cl−稳态中的作用。 SARS-CoV-2包膜蛋白通过增加细胞内Cl−浓度损害气道上皮屏障功能并加重气道炎症研究结论 03 总之，SARS-CoV-2 E蛋白下调紧密连接蛋白，破坏气道上皮屏障的完整性。此外，E蛋白通过TLR2/4-JNK-AP-1信号通路上调PDE4表达，显著降低细胞内cAMP水平，导致CFTR介导的Cl−转运受损。本研究结果为E蛋白促进气道上皮细胞内Cl−水平的积累，从而加剧炎症反应提供了新的视角。旨在提高cAMP水平以打开CFTR的治疗干预，或使用CFTR拮抗剂和SGK1抑制剂以消除细胞内炎症级联反应的治疗干预，可能有望减轻SARS-CoV-2诱导的气道炎症。参考资料： https://www.nature.com/articles/s41392-024-01753-z 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｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

临床结果紧急使用授权临床研究

2024-03-26

·生物探索

STTT | 广州医科大学钟南山团队发现在SARS-CoV-2感染期间气道上皮损伤和持续气道炎症中的新致病机制

引言SARS-CoV-2感染破坏上皮屏障并引发气道炎症。冠状病毒的核心毒力结构成分包膜(E)蛋白可能在这一过程中发挥作用。病原体可能通过破坏囊性纤维化跨膜传导调节剂(CFTR)来干扰Cl-的经上皮转运，CFTR调节核因子κB (NF-κB)信号。然而，SARS-CoV-2 E蛋白对气道上皮屏障功能、Cl−转运和强烈炎症反应的病理影响仍有待阐明。2024年3月25日，广州医科大学钟南山团队在Signal Transduction and Targeted Therapy（IF 39）在线发表题为”SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl− concentration“的研究论文，该研究证明了E蛋白下调紧密连接蛋白的表达，导致气道上皮屏障的破坏。E蛋白通过上调气道上皮细胞磷酸二酯酶4D (PDE4D)表达，激活Toll样受体(TLR) 2/4和下游c-Jun N末端激酶(JNK)信号，导致细胞内Cl−浓度([Cl−]i)升高。这种升高的[Cl−]i通过促进血清/糖皮质激素调节激酶1 (SGK1)的磷酸化而导致气道炎症加剧。此外，阻断SGK1或PDE4可减轻E蛋白诱导的强烈炎症反应。总的来说，这些发现为SARS-CoV-2 E蛋白在SARS-CoV-2感染期间气道上皮损伤和持续气道炎症中的致病作用提供了新的见解。SARS-CoV-2是导致COVID-19大流行的病原体，对全球公共卫生构成了重大挑战。SARS-CoV-2可能破坏肺泡上皮屏障，引发气道炎症加剧，导致呼吸困难，严重时进展为急性呼吸衰竭。然而，上皮屏障功能破坏和炎症增强的确切分子机制尚不完全清楚。了解SARS-CoV-2的致病机制有助于确定临床干预的新靶点。SARS-CoV-2是一种包膜病毒，具有正义单链RNA基因组。该病毒可破坏上皮细胞的完整性，加剧呼吸道上皮细胞的炎症，这是抵御病毒感染的第一道防线。SARS-CoV-2编码四种结构蛋白——刺突蛋白(S)、包膜蛋白(E)、膜蛋白(M)和核衣壳蛋白(N)。S蛋白介导病毒与宿主受体血管紧张素转换酶2 (ACE2)的结合和病毒与细胞膜的融合。M蛋白在病毒组装中起着至关重要的作用，而N蛋白对病毒基因组的包装和存活至关重要。值得注意的是，E蛋白是一种核心结构毒力因子，在维持病毒生命周期(如病毒组装)中起着至关重要的作用。一些研究探索了SARS-CoV-2 S、M和N蛋白的致病作用。然而，SARS-CoV-2 E蛋白在上皮紧密连接和粘膜炎症中的作用和机制尚不清楚。气道屏障由紧密连接、纤毛粘液清除和免疫细胞组成。紧密连接是由claudin家族跨膜蛋白组成的超分子实体，通过含有支架蛋白的细胞质PDZ结构域与肌动蛋白细胞骨架相连。紧密连接通过维持粘膜单层的完整性和细胞极性，建立物理屏障，调节分子的细胞旁通透性，调节先天免疫。然而，在呼吸道病毒感染期间，由于紧密连接蛋白的表达失调，屏障功能可能受损，导致入侵的病原体进入上皮下间隙。先前的研究表明，SARS-CoV-2的高病毒载量可破坏气道上皮紧密连接，部分涉及与Lin-7-1相关蛋白(PALS1)的相互作用。此外，SARS-CoV-2 E蛋白还可能与紧密连接蛋白zona occluden-1 (ZO-1)相互作用，导致上皮紧密连接损伤。这些观察结果表明，SARS-CoV-2 E蛋白在触发上皮屏障功能障碍中起关键作用。纤毛粘膜清除在维持气道微环境的稳态，确保有效清除入侵病原体方面起着至关重要的作用。纤毛黏液清除的有效性部分取决于水和离子运输的动力学。氯离子(Cl−)是人体内的主要阴离子，细胞内的Cl−浓度([Cl−]i)受到多种Cl−通道和转运体的严格调控。最近的证据表明，细胞内Cl-可能调节信号，细胞内Cl-稳态的破坏可能与多种细胞功能的改变有关，如炎症和免疫紊乱。模式图（Credit: Signal Transduction and Targeted Therapy）因此，细胞内Cl−的积累可能在病原体(如病毒)感染后持续气道炎症的放大中发挥重要作用。囊性纤维化跨膜传导调节剂(CFTR)是一种3'，5' -环单磷酸盐(cAMP)激活的Cl-通道，表达于全身上皮细胞的顶端膜。在上皮细胞中，各种病原体的感染可导致CFTR表达降低或功能障碍，导致阴离子分泌受损，细胞内Cl−失衡。有趣的是，CFTR和TMEM16介导的Cl-外排参与了SARS-CoV-2的进入和复制，这表明细胞内Cl-信号在SARS-CoV-2感染过程中发挥了作用。Toll样受体(TLRs)是一种模式识别受体(PRRs)，通过识别病原体相关分子模式(PAMPs)在感染过程中启动炎症反应和先天防御反应。研究证实TLR2能够识别SARS-CoV-2的S蛋白和E蛋白，在COVID-19的发生发展中发挥了至关重要的作用。丝裂原活化蛋白激酶(MAPK)级联是高度保守的信号分子，负责将细胞外刺激转导为细胞信号。哺乳动物细胞中有三种主要的MAPK通路，包括细胞外信号调节激酶(ERK，也称为p42/p44 MAPK)、c-Jun N-末端激酶(JNK，也称为应激激活蛋白激酶，SAPK)和p38激酶。MAPK通路已被证明可被多种病毒激活，因此是缓解病毒诱导的炎症细胞因子风暴的关键靶点。因此，研究TLR信号通路和MAPK通路在SARS-CoV-2感染过程中的参与可能有助于阐明COVID-19的免疫发病机制，并探索有价值的抗病毒治疗靶点。因此，该研究旨在探讨SARS-CoV-2 E蛋白对气道上皮完整性和炎症反应的病理影响及其潜在机制。原文链接https://www.nature.com/articles/s41392-024-01753-z责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

临床结果临床研究紧急使用授权

2024-03-26

·BioSpace

Thryv Therapeutics to Present Results of Wave I Part 1 Clinical Study at American College of Cardiology Conference in Atlanta, Georgia on April 7th, 2024

Treatment with LQT-1213 demonstrated statistically significant and clinically meaningful reductions in dofetilide-induced QTc prolongation. Larger treatment effects seen in pre-defined subgroups of individuals with largest increases in QTc from baseline and longest QTc intervals. No meaningful safety findings, including no effects on ECG morphology. MONTREAL, March 26, 2024 /PRNewswire/ - Thryv Therapeutics is pleased to announce the presentation of its poster: SGK1 inhibitor LQT-1213 significantly attenuates dofetilide-induced QT prolongation in humans: Results of the WAVE I Clinical Study at the American College of Cardiology Conference. Thryv's poster presentation will be presented on Sunday, April 7th from 12:15 p.m. - 1:00 p.m. in Hall B4-5. Representatives from Thryv will also be present throughout the weekend to meet with cardiologists and electrophysiologists to gain insights into various elements of their development program strategies. To learn more about this initiative, please contact admin@thryvtrx.com. The WAVE I proof of concept clinical study evaluated LQT-1213 for the reduction of QTcF in individuals with dofetilide-induced long QT Syndrome ("LQTS"). LQT-1213 is a potent and selective inhibitor of Serum Glucocorticoid inducible Kinase 1 (SGK1), which is implicated in QTc prolongation. In the WAVE I study, following two days of treatment with dofetilide (baseline) – an agent known to prolong QTc – individuals with meaningful increases in their QTc interval received six days of increasing LQT-1213 doses with a consistent dose of dofetilide. Individuals were continuously monitored and received regular ECGs to assess the safety and efficacy of LQT-1213. Mean reductions of QTcF from baseline (measured as QTcF) were statistically significant beginning with the first evaluable time point of the primary analysis and were sustained during the peak dofetilide-induced prolongation. In a predefined subset of individuals who experienced larger dofetilide-induced prolongation of QTcF, individuals treated with LQT-1213 achieved more robust, clinically meaningful reductions of QT consistent with scientific evidence of SGK1 activation in LQTS. LQT-1213 was well tolerated with no serious adverse events or treatment-related study discontinuations. No QTcF over-shortening was observed in the study. There were no observed changes in ECG morphology, heart rate or blood pressure. Part 2 of the WAVE I clinical study is currently enrolling a small cohort of individuals with genetically confirmed congenital Long QT Syndrome Type 2 and Type 3. This study will provide information about the safety of LQT-1213 before initiation of Phase 3 clinical studies in congenital LQTS patients. Data from this study is expected in the second quarter of 2024. More about the WAVE I (Parts 1 and 2) can be found at . Long QT Syndrome, or LQTS, is a disorder of the heart's electrical system causing the lower chambers of the heart to contract and release too slowly. LQTS can be either congenital or acquired. Congenital LQTS is a set of rare orphan diseases in which people are genetically predisposed to chronic prolongation of their QTc interval (commonly more than 480 milliseconds), leading to increased risk of torsades de pointes, a lethal cardiac arrhythmia that causes sudden cardiac death. Acquired Long QT may develop from the administration of therapies which block electrical pathways in the heart, leading to a similar mechanistic prolongation of QT and risk of sudden cardiac death. 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).

临床结果临床1期