A Phase 1, Open-label Study to Investigate the Pharmacokinetics and Metabolism of GLPG3970 in Healthy Male Subjects Following a Single Oral Dose of GLPG3970 Relative to an Intravenous [14C]GLPG3970 Microtracer and Single Oral [14C]GLPG3970 Administration

A study in healthy male volunteers to assess how the radiolabelled test medicine is taken up and broken down by the body when given by short infusion into a vein and when given by the mouth in the form of a tablet and an oral solution.

开始日期2021-06-07

申办/合作机构

Galapagos NV

NCT04700280 / Terminated临床2期

A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered GLPG3970 for 12 Weeks in Adult Subjects With Active Primary Sjögren's Syndrome

This is a first exploration of GLPG3970 in participants with active primary Sjogren's Syndrome (pSS) to evaluate the efficacy, safety and tolerability and to determine its pharmacokinetics (PK) profile compared to placebo.

开始日期2021-01-28

申办/合作机构

Galapagos NV

100 项与 SIK3 x SIK2 相关的临床结果

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100 项与 SIK3 x SIK2 相关的转化医学

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0 项与 SIK3 x SIK2 相关的专利（医药）

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项与 SIK3 x SIK2 相关的文献（医药）

2024-08-27·Endocrinology

SIK2 and SIK3 Differentially Regulate Mouse Granulosa Cell Response to Exogenous Gonadotropins In Vivo

Article

作者: Foretz, Marc ; Lakomy, Oliwia ; Filzen, Rachael ; Tsumaki, Noriyuki ; Stocco, Carlos ; Hassan, Mariam ; Takemori, Hiroshi ; Armouti, Marah ; Hayes, Emily T

AbstractSalt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles. This study hypothesizes that SIK2 and SIK3 differentially regulate follicle growth and fertility via contrasting actions in the granulosa cells (GCs), the somatic cells of the follicle. Therefore, SIK2 or SIK3 GC-specific knockdown (SIK2GCKD and SIK3GCKD, respectively) mice were generated by crossing SIK floxed mice with Cyp19a1pII-Cre mice. Fertility studies revealed that pup accumulation over 6 months and the average litter size of SIK2GCKD mice were similar to controls, although in SIK3GCKD mice were significantly lower compared to controls. Compared to controls, gonadotropin stimulation of prepubertal SIK2GCKD mice resulted in significantly higher serum estradiol levels, whereas SIK3GCKD mice produced significantly less estradiol. Cyp11a1, Cyp19a1, and StAR were significantly increased in the GCs of gonadotropin-stimulated SIK2GCKD mice. However, Cyp11a1 and StAR remained significantly lower than controls in SIK3GCKD mice. Interestingly, Cyp19a1 stimulation in SIK3GCKD was not statistically different compared to controls. Superovulation resulted in SIK2GCKD mice ovulating significantly more oocytes, whereas SIK3GCKD mice ovulated significantly fewer oocytes than controls. Remarkably, SIK3GCKD superovulated ovaries contained significantly more preantral follicles than controls. SIK3GCKD ovaries contained significantly more apoptotic cells and fewer proliferating cells than controls. These data point to the differential regulation of GC function and follicle development by SIK2 and SIK3 and supports the therapeutic potential of targeting these kinases for treating infertility or developing new contraceptives.

2024-04-11·Journal of Medicinal Chemistry1区 · 医学

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

1区 · 医学

Article

作者: Delachaume, Carole ; Amantini, David ; Laenen, Wendy ; Monjardet, Alain ; Dupont, Sonia ; Roca Magadan, Carlos ; Peixoto, Christophe ; Dos Santos, Aurélie ; Merciris, Didier ; Wakselman, Emanuelle ; Andrews, Martin ; Lavazais, Stephanie ; Desroy, Nicolas ; Jary, Hélène ; Borgonovi, Monica ; López-Ramos, Miriam ; Bucher, Denis ; Joncour, Agnes ; Pereira Fernandes, Anna ; Saccomani, Corinne ; Temal-Laib, Taouès ; Jimenez, Juan-Miguel ; De Vos, Steve ; Tirera, Amynata ; Brys, Reginald ; Drennan, Michael

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (32), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC₅₀ of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline efforts made to increase selectivity against SIK1 and improve CYP time-dependent inhibition properties through the structure-activity relationship. The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models.

2024-01-11·Journal of Medicinal Chemistry1区 · 医学

Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312

1区 · 医学

Article

作者: Pereira Fernandes, Anna ; Lavazais, Stephanie ; Sartori, Eric ; Bucher, Denis ; Flower, Thomas ; Amantini, David ; López-Ramos, Miriam ; Bonnaterre, Florence ; De Vos, Steve ; Mollat, Patrick ; Touitou, Robert ; Borgonovi, Monica ; Laenen, Wendy ; Bienvenu, Natacha ; Bugaud, Olivier ; Roca Magadán, Carlos ; Desroy, Nicolas ; Picolet, Olivier ; De Lemos, Elsa ; Andrews, Martin ; Peixoto, Christophe ; Temal-Laib, Taouès ; Gosmini, Romain ; Brys, Reginald ; Monjardet, Alain

Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine kinases and form a subfamily of the protein kinase AMP-activated protein kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune cells and mouse models has been associated with a dual mechanism of action consisting of a reduction of pro-inflammatory cytokines and an increase of immunoregulatory cytokine production, suggesting a therapeutic potential for inflammatory diseases. Following a high-throughput screening campaign, subsequent hit to lead optimization through synthesis, structure-activity relationship, kinome selectivity, and pharmacokinetic investigations led to the discovery of clinical candidate GLPG3312 (compound 28), a potent and selective pan-SIK inhibitor (IC₅₀: 2.0 nM for SIK1, 0.7 nM for SIK2, and 0.6 nM for SIK3). Characterization of the first human SIK3 crystal structure provided an understanding of the binding mode and kinome selectivity of the chemical series. GLPG3312 demonstrated both anti-inflammatory and immunoregulatory activities in vitro in human primary myeloid cells and in vivo in mouse models.

项与 SIK3 x SIK2 相关的新闻（医药）

2023-05-06

·生物谷

Pharmacol Res：科学家找到了与肝癌患者生存率显著相关的靶点

LKB1（肝激酶B1）信号通路已被证明在调节能量稳态、极性和代谢等关键细胞过程中发挥着不可或缺的作用。 LKB1（肝激酶B1）信号通路已被证明在调节能量稳态、极性和代谢等关键细胞过程中发挥着不可或缺的作用。早期研究将LKB1从人类胎肝中分离出来，发现它具有抑癌作用，其突变与遗传性癌症障碍Peutz-Jeghers综合征有关。进一步的研究确定LKB1是一种主激酶，它通过与CAB39和STRAD支架作用来磷酸化16种下游激酶（AMPK1/2、MARK1/2/3/4、NUAK1/2、SIK1/2/3、BRSK1/2和SNRK），从而对细胞生物学产生影响。尽管LKB1信号轴的部分，如AMPK途径，已经得到了很好的研究和报道，但LKB1直接下游的许多激酶仍然没有得到充分的表征。图片来源：https://doi.org/10.1016/j.phrs.2023.106757 近日，来自杜兰大学的研究者们在Pharmacol Res.杂志上发表了题为“LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma”的文章，该研究表明LKB1下游的许多激酶对肝癌患者生存率有统计学显著影响。 LKB1、STRAD和CAB39形成一种复合物，其功能是磷酸化和激活下游信号通路。有趣的是，所有复杂成员的mRNA水平都与患者生存率呈正相关，但只有STRADß和CAB39L具有统计学意义。这可以通过LKB1在恶性细胞细胞谢改变中的作用来解释。除了支架蛋白外，具有统计学正生存相关性的下游LKB1激酶是SIK1、SIK2和SNRK。 GEPIA的其他生物信息学分析还发现，与正常肝组织相比，癌症中SIK1的表达减少了2倍。通过蛋白质印迹进行的蛋白质表达分析未能产生任何SIK1条带，进一步支持SIK1在肝细胞癌中的肿瘤抑制作用。此外，SIK3的患者生存风险比范围为0.52-1.03。该值被加权为正相关，但在统计上不显著。尽管如此，似乎与正生存率有着趋势性的相关性。肝细胞癌细胞系的蛋白质印迹分析显示高表达水平（Huh7和Hep3B）和无表达水平（HepG2和PLC/PRF/5）之间存在明显的二分法，表明存在肝细胞癌亚型的可能性。相反，AMPKα2、MARK2、BRSK1和BRSK2与肝细胞癌的不良生存结果具有统计学显著相关性。GEPIA分析表明，AMPKα2、BRSK1和BRSK2在正常肝组织中低表达。与正常组织相比，肝脏肿瘤中的AMPKα2和BRSK1分别扩增了5倍和2倍。免疫印迹分析显示癌症细胞中AMPKα2和MARK2的高水平表达。此外，AMPKα2、MARK2和BRSK2已被证明分别在肝细胞癌、非小细胞肺癌和胰腺癌的营养缺乏条件下通过Warburg效应促进肿瘤活性和生长。影响肝癌患者生存率的下游激酶。图片来源：https://doi.org/10.1016/j.phrs.2023.106757 综上所述，STRADß、CAB39L、AMPKα、MARK2、SIK1、SIK2、BRSK1、BRSK2和SNRK的表达对肝癌患者生存率有统计学显著影响。该综述旨在解决下游LKB1激酶在知识方面的差距，并为他们在肝细胞癌发生中的潜在作用奠定基础。（生物谷 Bioon.com）参考文献 Khoa Nguyen et al. LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma. Pharmacol Res. 2023 Apr 4;106757. doi: 10.1016/j.phrs.2023.106757.

信使RNA

2023-02-24

·Endpoints

Galapagos goes 0-for-3 on inflammation program as it cuts an early-stage candidate

Galapagos has cut anti-inflammatory drug candidate GLPG4399 following the completion of an early-stage healthy volunteer trial, according to its 2022 annual report released Thursday afternoon. GLPG4399 was a SIK3 inhibitor, one in a line of such salt-inducible kinase (SIK) inhibitors that Galapagos has been trying to develop for inflammatory diseases like rheumatoid arthritis and ulcerative colitis. Originally, the biotech had been planning to move the drug forward in a study with rheumatoid arthritis patients in the middle of this year, but now it’s halting the program and going back to search for new SIK inhibitors. “Medicinal chemistry activities to identify SIK inhibitors with improved pharmacology continues,” Galapagos noted briefly in its press release. GLPG4399 was the third SIK inhibitor Galapagos brought out of the clinic — all part of a franchise Galapagos dubbed Toledo. The first candidate, GLPG3312, similarly only made it through healthy volunteer studies before Galapagos scrapped it. The second, GLPG3970, disappointed in Phase II trials in ulcerative colitis and rheumatoid arthritis, and though it showed some signs of efficacy in psoriasis, Galapagos opted to toss that candidate as well. The small pipeline prune comes after Galapagos laid off 200 staffers and discontinued work on its fibrosis and kidney disease programs, cuts that followed a long string of setbacks at the biotech. In December, Galapagos also announced that its chief business officer André Hoekema and chief medical officer Walid Abi-Saab are retiring, though the latter is remaining with the company until the end of May. Galapagos shares $GLPG fell almost 8% after the markets opened Friday. The biotech did not immediately return request for comment.

临床2期临床失败

2022-12-26

·生物谷

PNAS：新型口服化合物或有望预防并治疗骨质疏松症

来自麻省总医院等机构的科学家们通过研究识别出了一种有潜力的化合物，其或能影响甲状旁腺素信号通路的组分，当给予小鼠口服时，还会增加机体的骨质量。甲状旁腺素（parathyroid hormone）能刺激骨形成，该激素的类似物也用于治疗骨质疏松症（osteoporosis）患者，然而这些药物只有在每天注射的情况下才会有效。近日，一篇发表在国际杂志Proceedings of the National Academy of Sciences上题为“Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice”的研究报告中，来自麻省总医院等机构的科学家们通过研究识别出了一种有潜力的化合物，其或能影响甲状旁腺素信号通路的组分，当给予小鼠口服时，还会增加机体的骨质量。这一研究发现或有望帮助研究人员开发出预防并治疗骨质疏松症的新型更为方便的药物。医学博士Marc Wein说道，目前并没有针对骨质疏松症的口服药物来刺激骨形成，于是我们就试图理解正常情况下能控制骨产生的通路，从而开发出诸如此类药物。参与甲状旁腺素的特殊通路或许会抑制盐诱导激酶2和3（SIK2和SIK3），这两种酶类在调节骨生长和重塑方面扮演着重要角色。新型口服化合物或有望预防并治疗骨质疏松症。图片来源：Proceedings of the National Academy of Sciences (2022). DOI:10.1073/pnas.2214396119 文章中，研究者Wein及其同事开发了针对这些酶类的新型结构模型，随后利用包括基于结构的药物设计和迭代药物化学等先进方法识别出了能潜在抑制SIK2和SIK3酶类功能的特殊化合物；当给予细胞（尤其是给予小鼠时）时，这种名为SK-124的化合物或许具有甲状旁腺素样的效应；在小鼠机体中，连续三周每天口服治疗一次或能增加机体血液中钙离子和维生素D的水平，同时还会增强机体的骨形成和骨量，同时也并不会产生短期的毒性效应。研究者指出，基于这些研究发现，我们提出，诸如SK-124等小分子或许能代表新一代的口服骨构建疗法来治疗骨质疏松症；目前研究人员正在与Radius Health公司合作，希望能进一步优化并开发治疗骨质疏松症患者的新型疗法。综上，本文研究结果表明，口服SIK2/SIK3抑制剂SK-124作为疗法进行治疗时或许会对机体骨骼和矿物质代谢产生甲状旁腺素样的效应。（生物谷Bioon.com）原始出处： Tadatoshi Sato,Christian D. Castro Andrade,Sung-Hee Yoon, et al. Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice, Proceedings of the National Academy of Sciences (2022). DOI:10.1073/pnas.2214396119