更新于：2024-11-01

GSK-3β

更新于：2024-11-01

基本信息

别名

糖原合酶激酶3β、glycogen synthase kinase 3 beta、Glycogen synthase kinase-3 beta

+ [3]

简介

Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:1846781, PubMed:9072970, PubMed:14690523, PubMed:20937854, PubMed:12554650, PubMed:11430833, PubMed:16484495). Requires primed phosphorylation of the majority of its substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:8397507). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:8397507). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (PubMed:14690523). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1 which enhances its antiviral activity (PubMed:22514281). Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation (PubMed:15448698, PubMed:15647282). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation (By similarity). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, stabilizing E2F1 and promoting its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) complex and FXR1 degradation by the proteasome (By similarity).

关联

项与 GSK-3β 相关的药物

Lithium succinate

靶点

GSK-3β x IMPA1 x mGluR3

作用机制

GSK-3β调节剂 [+2]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

英国

首次获批日期1990-01-01

Lithium Citrate

柠檬酸锂

靶点

BACE1 x GSK-3β

作用机制

BACE1抑制剂 [+2]

在研机构

Medesis Pharma SA [+1]

原研机构

Solvay SA

在研适应症

阿尔茨海默症

非在研适应症

躁郁症

最高研发阶段临床2期

首次获批国家/地区

美国

首次获批日期1980-12-23

Elraglusib

靶点

GSK-3 x GSK-3β

作用机制

GSK-3抑制剂 [+1]

在研机构

Actuate Therapeutics, Inc.初创企业 [+7]

原研机构

University of Illinois

在研适应症

转移性黑色素瘤 [+29]

非在研适应症

慢性淋巴细胞白血病 [+11]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

167

项与 GSK-3β 相关的临床试验

NCT04832438 / Withdrawn临床2期

Phase 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3 Beta (GSK 3β) Inhibitor, Plus Carboplatin in Patients With Advanced, Metastatic Salivary Gland Carcinoma

9-ING-41 is a small molecule potent selective GSK-3β inhibitor with antitumor activity. This study investigates 9-ING-41 in combination with carboplatin chemotherapy in patients with incurable, recurrent or metastatic salivary gland carcinomas (SGC). Patients with advanced SGC (including all histologic subtypes and adenoid cystic carcinoma [ACC]) will receive 9-ING-41 intravenously (IV) along with carboplatin IV at standard dosing together on Day 1, and 9-ING-41 alone on Day 4 of a 21-day cycle. Participants will be enrolled to two histologic cohorts: Cohort 1 will be comprised of those with ACC, and Cohort 2 will include patients with non-ACC SGC (or all other salivary gland cancer histologies). Treatment will continue until progression of disease, death, or discontinuation of therapy for any reason.

开始日期2030-12-18

申办/合作机构

Actuate Therapeutics, Inc.初创企业

NCT05105958 / Not yet recruiting临床2期IIT

Tideglusib for the Treatment of Amyotrophic Lateral Sclerosis (TIDALS): a Randomized Placebo-controlled Phase II Trial

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition, mainly characterized by progressive weakness and wasting of the limbs, the respiratory and bulbar muscles. Respiratory insufficiency leads to a fatal outcome after a mean diseases duration of only three to five years. The disease is characterized by pathological accumulations of a protein called TDP-43, which can be found large cortical and sub-cortical areas of post-mortem ALS brains.
No causal treatment for this condition is known to date, and there is a large unmet need to develop new strategies in order to halt or slow down its progression.
The aim of this study is to test the safety and tolerability of Tideglusib, a treatment that is already in clinical trials for other neuromuscular conditions, in patients with ALS. It is assumed that this drug may have a significant therapeutic benefit in this population due to his mode of action: In the ALS mouse model, Tideglusib decreases significantly the amount of accumulated TDP-43 proteins within the cells.

开始日期2025-12-01

申办/合作机构

Les Hôpitaux Universitaires de Genève

[+4]

ISRCTN12858621 / RecruitingN/AIIT

Lithium orotate: a potential accessible supplement for people experiencing depression with mixed features.

开始日期2024-10-28

申办/合作机构-

100 项与 GSK-3β 相关的临床结果

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100 项与 GSK-3β 相关的转化医学

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0 项与 GSK-3β 相关的专利（医药）

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8,309

项与 GSK-3β 相关的文献（医药）

2025-01-01·Brain Research

Emoxypine succinate modulates behavioral and molecular responses in zebrafish model of iron Overload-Induced neuroinflammation via CDK5/GSK3- β and NLRP3 inflammasome pathway

Article

作者: Bagwe Parab, Siddhi ; Kaur, Ginpreet

Excessive iron accumulation in the brain plays a significant role in neurodegenerative processes, contributing to the pathogenesis of Alzheimer's disease (AD). AD, a prominent neurological disorder affecting the central nervous system, is characterized by the accumulation of beta-amyloid (Aβ) and tau phosphorylation. This accumulation leads to the subsequent development of cognitive impairments, particularly in learning and memory functions. This study investigates the neuroprotective effects of emoxypine succinate in a zebrafish model of iron overload-induced neurodegeneration. Iron was administered to the zebrafish for 28 days to induce neurodegeneration. Following induction, Emoxypine succinate was employed as a treatment intervention for 14 days (concentrations of 4 mg/L, 8 mg/L, and 12 mg/L). Following the end of the treatment, behavioral tests (Y maze test, Novel tank test) were conducted on the zebrafish, and the biochemical (MDA, Catalase, SOD, GSH) and molecular parameters (AchE, Iron levels, IL-1β, TNF-α, CDK-5, GSK-3β, and NLRP3) of the zebrafish brain were also assessed. In the novel tank test, emoxypine succinate-treated groups exhibited significantly increased time in the upper zone (p < 0.001), higher distance travelled (p < 0.001), and shorter latency to the top (p < 0.001) compared to the negative control. Similarly, the Y-maze test revealed improved time in the novel arm (p < 0.001) and total distance travelled (p < 0.001) in treated groups versus the negative control. Assessment of oxidative stress parameters demonstrated significant reductions in oxidative stress in emoxypine succinate-treated groups. Furthermore, AChE activity decreased significantly (p < 0.001), and brain iron levels decreased substantially (p < 0.001) in treated groups, indicating positive therapeutic outcomes. Molecular analysis showed a significant reduction in pro-inflammatory markers like IL-1β, TNF-α, CDK-5, GSK-3β, and NLRP3 (p < 0.001). This comprehensive study highlights the potential efficacy of emoxypine succinate in mitigating neurodegeneration associated with iron dysregulation.

2025-01-01·Behavioural Brain Research

Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation

Review

作者: Mannan, Ashi ; Mohan, Maneesh ; Nauriyal, Aayush ; Singh, Thakur Gurjeet

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.

2025-01-01·Behavioural Brain Research

Novel insights into famotidine as a GSK-3β inhibitor: An explorative study in aluminium chloride-induced Alzheimer’s disease rat model

Article

作者: Sequeira, Ronnita C ; Godad, Angel

Alzheimer's disease (AD), a chronic neurodegenerative disease, presents a substantial global health challenge. This study explored the potential therapeutic role of famotidine, a histamine (H2) receptor antagonist, as a glycogen synthase kinase-3β (GSK-3β) inhibitor in the context of AD induced by aluminium chloride (AlCl₃) in a rat model. The intricate relationship between GSK-3β dysregulation and AD pathogenesis, particularly in amyloid-β (Aβ) production, formed the basis for investigating famotidine's efficacy. Molecular modelling revealed famotidine's efficient binding to GSK-3β, suggesting inhibitory potential. In behavioural assessments, famotidine-treated groups exhibited dose-dependent improvements in Morris Water Maze, Novel Object Recognition, and Y-Maze tests, comparable to the standard Rivastigmine tartrate group. Biochemical analyses showed that famotidine inhibits acetylcholinesterase, decreases lipid peroxidation, increases antioxidant activity, and mitigates oxidative stress. Moreover, famotidine significantly lowered the levels of GSK-3β, IL-6, and Aβ(1-42). The neuroprotective effects of famotidine were further supported by histopathological analysis. This comprehensive investigation underscores famotidine's potential as a GSK-3β inhibitor, providing insights into its therapeutic impact on AD induced by AlCl₃. The study offers a promising avenue for repurposing famotidine due to its established safety profile and widespread availability, highlighting its potential in addressing the formidable challenge of AD.

项与 GSK-3β 相关的新闻（医药）

2024-10-29

·奇点网

这是给CD8+T细胞上缚地之术啊

*仅供医学专业人士阅读参考这届网友的造词能力，有时候是真让奇点糕拍案叫绝，比如最近挺火的就业“吉祥三保”，奇点糕第一次见可真没想到是保安+保姆+保洁的意思。而跟吉祥三保连着的，经常是什么“人生少走四十年弯路”的调侃，不过到底走没走弯路还两说呢，比如保安就不能乱当，人体里那些给癌细胞当保安当门卫的免疫细胞，不就变成为虎作伥了？近日，中山大学吴艳、郑利民团队在Journal for ImmunoTherapy of Cancer期刊发表的研究成果[1]，就揭示了肝细胞癌（HCC）微环境中存在一类给肿瘤当“门卫”的单核细胞，它们的特征是主要分布在肿瘤边缘且表达CD93，并分别通过产生多能蛋白聚糖（versican）和上调PD-L1表达两种方式，阻止CD8+T细胞向肿瘤浸润和有效激活，简直了啊。论文首页截图HCC微环境的极强免疫抑制性可以称得上臭名昭著，而中山大学研究者们早就发现，单核细胞正是上调PD-L1表达最显著，介导免疫抑制的主要“战犯”之一[2]，不过随着空间组学分析时代的到来，看到单核细胞和CD8+T细胞往往都分布在肿瘤边缘，研究者们有了新的猜想：单核细胞发挥免疫抑制的机制，或许还包括阻拦CD8+T细胞向肿瘤内浸润。而把CD93和单核细胞联系在一起，则是因为此前有研究显示CD93可能参与HCC常见的异常新生血管形成，以它为干预靶标有望重塑微环境、增敏免疫治疗[3]；研究者们在分析HCC内表达CD93的细胞时意外发现，瘤周部位单核/巨噬细胞也存在CD93的高表达，且表达水平仅次于参与血管形成的血管内皮细胞，甚至还与患者生存预后较差显著相关。HCC瘤周部位存在大量高表达CD93的单核细胞，且这一现象与患者不良预后有关既然如此，接下来探索单核细胞高表达CD93的原因和影响就顺理成章了。同样是基于既往研究[4]的发现，研究者们推测使单核细胞上调CD93表达的可能是糖酵解，并在细胞实验中证实，HCC细胞培养上清液可通过激活Erk信号，一过性上调单核细胞的CD93表达，而阻断糖酵解（使用2-DG或PFKFB3酶抑制剂3PO）即可消除这种效应。研究者们又用小干扰RNA（siRNA）精准沉默了单核细胞的CD93，发现HCC细胞培养上清液处理所导致的单核细胞PD-L1表达上调，会在CD93被沉默后不见踪影，且PD-L1 mRNA水平并无明显改变，提示CD93的调控是在转录后发生的；进一步分析显示，CD93可通过激活AKT-GSK3β信号通路，增强PD-L1的磷酸化水平以减少其降解。CD93可通过转录后调节机制，在癌细胞影响下上调单核细胞PD-L1表达水平但CD93的影响还不止于此，在分析沉默CD93后表达水平显著改变的基因时，研究者们发现了编码多能蛋白聚糖的VCAN基因（仅有的2个与外部HCC单细胞测序结果重合的基因之一），而多能蛋白聚糖一般是细胞外基质的重要组分，且也会在HCC细胞培养上清液处理后表达显著上调，怎么看都不像什么好东西。于是借助免疫组化染色，研究者们评估了HCC微环境中表达VCAN基因细胞的分布情况，结果还真就和前面的CD93+单核细胞基本重合，即VCAN表达也集中在瘤周部位，且主要见于单核/巨噬细胞（以及部分成纤维细胞），多能蛋白聚糖的表达水平也与瘤内CD8+T细胞浸润数量负相关。体外Transwell迁移实验证实，多能蛋白聚糖能与细胞外基质的另外两种主要成分——I型胶原和透明质酸联手，大幅降低CD8+T细胞的迁移和穿透能力，这就解释了大部分CD8+T细胞为什么只能和CD93+单核细胞一起停留在HCC瘤周部位，无法有效向肿瘤内浸润。最后研究者们也通过实验确认，以siRNA沉默单核细胞的CD93确实可与PD-1/L1抑制剂实现协同增效，这就又是一条HCC免疫联合治疗的新路子了。由CD93+单核细胞产生的多能蛋白聚糖，会显著降低CD8+T细胞向HCC内的浸润能力参考文献：[1]Jiang D, Huang A, Zhu B X, et al. Targeting CD93 on monocytes revitalizes antitumor immunity by enhancing the function and infiltration of CD8+ T cells[J]. Journal for ImmunoTherapy of Cancer, 2024, 12(10): e010148.[2]Kuang D M, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1[J]. Journal of Experimental Medicine, 2009, 206(6): 1327-1337.[3]Sun Y, Chen W, Torphy R J, et al. Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy[J]. Science Translational Medicine, 2021, 13(604): eabc8922.[4]Peng Z P, Jiang Z Z, Guo H F, et al. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma[J]. Journal of Hepatology, 2020, 73(4): 906-917.本文作者丨谭硕

免疫疗法siRNA

2024-10-15

·PRNewswire

Metastatic Castration-Sensitive Prostate Cancer Clinical Trial Pipeline Insights Featuring 35+ Companies | DelveInsight

Metastatic castration-sensitive prostate cancer (mCSPC), also known as metastatic hormone-sensitive prostate cancer (mHSPC), refers to prostate cancer that has spread beyond the prostate but still responds to therapies that lower testosterone (castration) with an aging population, the incidence of prostate cancer is rising, leading to an increased demand for advanced therapies to treat metastatic forms of the disease. LAS VEGAS, Oct. 15, 2024 /PRNewswire/ -- DelveInsight's ' Metastatic Castration-Sensitive Prostate Cancer Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline mCSPC therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the mCSPC pipeline domain. Key Takeaways from the Metastatic Castration-Sensitive Prostate Cancer Pipeline Report DelveInsight's mCSPC pipeline report depicts a robust space with 35+ active players working to develop 40+ pipeline therapies for mCSPC treatment. Key mCSPC companies such as Tavanta Therapeutics, AstraZeneca, Regeneron Pharmaceuticals, Astellas Pharma, Propella Therapeutics, POINT Biopharma, Amgen, Janssen Research & Development, LLC, Bayer, Beigene, Amgen, Merck Sharp & Dohme LLC, Jiangsu HengRui Medicine Co., Ltd., Suzhou Kintor Pharmaceutical Inc, Astellas Pharma, and others are evaluating new mCSPC drugs to improve the treatment landscape. Promising mCSPC pipeline therapies such as TAVT-45 (abiraterone acetate), Saruparib (AZD5305), Capivasertib, REGN2810, Abiraterone decanote + dexamethasone or prednisone (PRL-02/ASP5541), [Ac-225]-PSMA-62, Xaluritamig, Apalutamide, Darolutamide, Luteinizing Hormone Releasing Hormone, Pembrolizumab, Dalpiciclib isethionate, GT0918, PRL-02, and others are under different phases of mCSPC clinical trials. In October 2024, Apalutamide (Erleada) was found to provide a significant improvement in overall survival (OS) at 24 months compared with enzalutamide (Xtandi) in the treatment of androgen receptor pathway inhibitor (ARPI)-naïve patients with metastatic castration-sensitive prostate cancer (mCSPC). In April 2024, Saruparib (AZD5305) demonstrated encouraging efficacy, favorable safety, a wide therapeutic index, and improved pharmacokinetic properties compared with currently approved PARP inhibitors in patients with advanced solid tumors harboring BRCA1/2, PALB2, or RAD51C/D mutations, according to findings from the Phase I/IIa PETRA study. In February 2024, Capivasertib combined with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer. Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3β. In January 2023, Tavanta Therapeutics announced positive top-line results from its pivotal, global Phase III clinical trial, evaluating the safety and efficacy of TAVT-45 (abiraterone acetate). The trial met its primary objective of establishing therapeutic equivalence of TAVT-45 to Zytiga® in patients with metastatic castrate-resistant prostate cancer (mCRPC) and metastatic high-risk castrate-sensitive prostate cancer (mCSPC), in addition to demonstrating a comparable safety profile. Request a sample and discover the recent advances in mCSPC treatment drugs @ Metastatic Castration-Sensitive Prostate Cancer Pipeline Report The mCSPC pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage mCSPC drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the mCSPC clinical trial landscape. Metastatic Castration-Sensitive Prostate Cancer Overview Metastatic castration-sensitive prostate cancer (mCSPC) is an advanced form of prostate cancer in which the cancer cells have spread beyond the prostate to other parts of the body, such as bones or lymph nodes, but remain responsive to hormone therapy. This means that reducing testosterone levels can still effectively slow the growth of cancer cells. mCSPC often arises when prostate cancer is initially diagnosed or when early-stage prostate cancer recurs after treatment. It is distinct from castration-resistant prostate cancer (CRPC), where the cancer continues to progress despite low testosterone levels. The causes of mCSPC primarily involve the spread of prostate cancer cells beyond the local prostate region, a process called metastasis. Although the exact mechanisms are complex, certain risk factors increase the likelihood of developing prostate cancer and its progression to metastatic disease. These risk factors include advanced age, a family history of prostate cancer, genetic mutations such as BRCA1/BRCA2, and race. Symptoms of mCSPC can include bone pain, urinary issues, fatigue, weight loss, and general malaise, especially if the cancer has spread to bones or lymph nodes. However, in many cases, early stages of metastasis may be asymptomatic, making regular screening essential for those at risk. Diagnosis of mCSPC typically involves a combination of blood tests, such as measuring prostate-specific antigen (PSA) levels, imaging studies, and biopsy to confirm the presence of cancer cells. Treatment for mCSPC revolves around androgen deprivation therapy to lower testosterone levels, often combined with other agents like chemotherapy (e.g., docetaxel) or second-generation androgen receptor inhibitors (e.g., abiraterone or enzalutamide). In recent years, clinical trials have shown the benefit of combining ADT with novel therapies to improve survival rates and manage symptoms, with personalized treatment approaches based on genetic testing becoming more common. Find out more about mCSPC treatment drugs @ Drugs for Metastatic Castration-Sensitive Prostate Cancer Treatment A snapshot of the mCSPC Pipeline Drugs mentioned in the report: Learn more about the emerging mCSPC pipeline therapies @ Metastatic Castration-Sensitive Prostate Cancer Clinical Trials Metastatic Castration-Sensitive Prostate Cancer Therapeutics Assessment The mCSPC pipeline report proffers an integral view of the mCSPC emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Metastatic Castration-Sensitive Prostate Cancer Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous Therapeutics Assessment By Molecule Type: Small molecule, Cell therapy, Peptides, Polymer, Small molecule, Gene therapy Therapeutics Assessment By Mechanism of Action: Steroidal inhibitor of CYP17A1, PARP1 inhibitor, Proto-oncogene protein c-akt inhibitors, CYP17 lyase inhibitor, Antibody-dependent cell cytotoxicity, Immunostimulants, T lymphocyte stimulants, Ionizing radiation emitters. Key Metastatic Castration-Sensitive Prostate Cancer Companies: Tavanta Therapeutics, AstraZeneca, Regeneron Pharmaceuticals, Astellas Pharma, Propella Therapeutics, POINT Biopharma, Amgen, Janssen Research & Development, LLC, Bayer, Beigene, Amgen, Merck Sharp & Dohme LLC, Jiangsu HengRui Medicine Co., Ltd., Suzhou Kintor Pharmaceutical Inc, Astellas Pharma, and others. Key Metastatic Castration-Sensitive Prostate Cancer Pipeline Therapies: TAVT-45 (abiraterone acetate), Saruparib (AZD5305), Capivasertib, REGN2810, Abiraterone decanote + dexamethasone or prednisone (PRL-02/ASP5541), [Ac-225]-PSMA-62, Xaluritamig, Apalutamide, Darolutamide, Luteinizing Hormone Releasing Hormone, Pembrolizumab, Dalpiciclib isethionate, GT0918, PRL-02, and others. Dive deep into rich insights for new drugs for mCSPC treatment, visit @ Metastatic Castration-Sensitive Prostate Cancer Drugs Table of Contents For further information on the mCSPC Cancer pipeline therapeutics, reach out @ Metastatic Castration-Sensitive Prostate Cancer Treatment Drugs Related Reports Metastatic Castration-Sensitive Prostate Cancer Market Metastatic Castration-Sensitive Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCSPC companies including Myovant Sciences, Pfizer, Bayer, Orion, Novartis, AstraZeneca, Pfizer, Janssen, Merck, Eli Lilly, among others. Metastatic Prostate Cancer Market Metastatic Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key metastatic prostate cancer companies including AstraZeneca, Arvinas, Madison Vaccines, Phosplatin Therapeutics, Hinova Pharmaceuticals, Bristol Myers Squibb, Merck, MacroGenics, Daiichi Sankyo, Seagen, Taiho Pharmaceutical, Modra Pharmaceuticals, Xencor, Point Biopharma, Lantheus Holdings, Zenith Epigenetics, Essa Pharma, Telix Pharmaceuticals, Kintor Pharmaceutical, AB Science, Eli Lilly and Company, Exelixis among others. Metastatic Castration-Resistant Prostate Cancer Market Metastatic Castration-Resistant Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCRPC companies including AstraZeneca, Merck Sharp & Dohme, Hinova Pharmaceuticals, Pfizer, Astellas Pharma, Modra Pharmaceuticals, AB Science, Eli Lilly and Company, Zr Pharma & GmbH, Bristol-Myers Squibb, Ipsen, Exelixis, Takeda, Janssen Research & Development, Tesaro, Lantheus Holdings, Kintor Pharmaceutical, MacroGenics, Daiichi Sankyo, Madison Vaccines, Novartis, Point Biopharma, Xencor, Essa Pharma, Telix International, Bayer, Arvinas, among others. Metastatic Castration-Resistant Prostate Cancer Pipeline Metastatic Castration-Resistant Prostate Cancer Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key mCRPC companies, including AstraZeneca, Merck Sharp & Dohme, Hinova Pharmaceuticals, Pfizer, Astellas Pharma, Modra Pharmaceuticals, AB Science, Eli Lilly and Company, Zr Pharma & GmbH, Bristol-Myers Squibb, Ipsen, Exelixis, Takeda, Janssen Research & Development, Tesaro, Lantheus Holdings, Kintor Pharmaceutical, MacroGenics, Daiichi Sankyo, Madison Vaccines, Novartis, Point Biopharma, Xencor, Essa Pharma , Telix International, Bayer, Arvinas, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期临床结果

2024-10-10

·CPHI制药在线

罗氏8.5亿美元收购锐格CDK管线，下一代CDK抑制剂之争蓄势待发

关注并星标CPHI制药在线 9月30日，锐格医药宣布已与罗氏旗下公司基因泰克就下一代CDK抑制剂达成收购协议。根据协议条款，基因泰克将以8.5亿美元的首付款收购锐格医药的下一代CDK抑制剂，锐格医药还有资格根据未来某些预定开发、监管和商业化里程碑的实现情况获得额外的现金付款。基因泰克将负责全球临床开发、生产和商业化工作。锐格医药将继续管理正在进行的两项I期试验直至完成。预计该交易将于2024年第四季度完成。目前，锐格医药管线中共2款在研CDK抑制剂，即RGT-419B、RGT-587。RGT-419B是锐格医药通过其自主知识产权的计算机加速药物设计平台CARD研制而成，为新一代CDK抑制剂，靶向CDK2/4/6，具有更加优化与平衡的激酶活性谱。RGT-419B对CDK2和CDK4具有亚纳摩尔级别的活性，同时对CDK6，9和GSK3β的选择性被控制在一定的范围内从而减少血液学和消化系统毒性。其个位数纳摩尔级别的CDK2激酶活性有利于克服Cyclin E/CDK2驱动的肿瘤耐药。 2022年2月11日，锐格医药RGT-419B的临床试验申请获得NMPA受理，为国内首个CDK2/4/6抑制剂。此前的2021年12月，RGT-419B已经获得FDA批准进行临床研究。去年12月，锐格医药宣布RGT-419B用于既往接受过CDK4/6抑制剂和内分泌治疗（ET）联合的HR+/HER2-晚期乳腺癌（ABC）患者获得积极的安全性和单药疗效数据。RGT-587是一款可穿越血脑屏障的CDK4选择性抑制剂，可用于治疗大脑转移瘤。下一代CDK抑制剂研发迫在眉睫在 HR+/HER2 - 类型的乳腺癌中，CDK4/6 途径常因 Cyclin D1 基因扩增或过表达、p16INK4a 基因突变或表达降低以及 Rb 蛋白功能丧失或异常磷酸化等机制异常激活，导致细胞周期失控、肿瘤增长。鉴于此，CDK4/6 成为乳腺癌治疗关键靶点，CDK4/6 抑制剂被开发并应用于临床，通过抑制 CDK4/6 的活性阻止 Rb 蛋白磷酸化，进而阻止细胞周期进程、抑制肿瘤细胞增殖。对于 HR 阳性 / HER-2 阴性晚期乳腺癌，内分泌治疗是主要方法，但会出现耐药情况。细胞周期蛋白依赖性激酶(CDK) 4/6 抑制剂的研发和批准显著改变了HR+/HER-2 阴性晚期乳腺癌的诊疗模式。自首款CDK4/6抑制剂哌柏西利（辉瑞）于2015年面世至今，全球已有5款CDK4/6抑制剂上市，其中有4款可用于治疗HR+/HER2-乳腺癌患者，分别是瑞波西利（Ribociclib）、哌柏西利（Palbociclib）、阿贝西利（Abemaciclib）、达尔西利（Dalpicilib）。虽然疗效明确，但是CDK4/6抑制剂面临的两大问题依然不容忽视。一个是耐药问题，几乎所有晚期患者和部分早期患者，在接受CDK4/6i联合内分泌治疗后会都产生耐药。研究发现CDK4/6抑制剂的耐药机制主要分为两类，一类是细胞周期特异性耐药机制，包括其它细胞周期调控相关蛋白功能异常，包括CDK4/6下游蛋白Rb1突变或缺失会导致CDK4/6抑制剂耐药，其它CDK蛋白例如CDK2被异常激活从而代偿性促进细胞周期转换，导致CDK4/6抑制剂耐药。还有一个是毒副作用。目前CDK4/6抑制剂最常见的不良反应是中性粒细胞减少，主要原因可能是因为对CDK6的抑制作用导致的。但基本上这种轻度骨髓抑制在停药一定时间后会自行恢复。下一代CDK抑制剂的开发目标主要是增效减毒，在克服CDK4/6抑制剂耐药的同时，减少脱靶毒性。热门靶点包括CDK2、CDK4等高选择性单靶点抑制剂，以及CDK2/4/6这样的多靶点抑制剂。 CDK4抑制剂：辉瑞领跑，恒瑞、百济竞速 CDK4/6抑制剂的临床治疗功效主要由CDK4驱动，而CDK6被认为更多与治疗毒性相关，于是CDK4作为升级版应运而生，有望改善有效性和安全性特征。CDK4抑制剂理论上比CDK4/6抑制剂毒性更低。CDK4i与ET联用在HR+、HER2-转移性乳腺癌患者中的早期临床探索试验中展现出良好的安全性和一定的有效性。然而目前尚无相关药物获批上市。全球范围内，据智慧芽数据库也仅三款药物进入临床阶段，分别为辉瑞的PF-07220060、恒瑞的HRS-6209和百济神州的BGB-43395。其中，PF-07220060已率先迈进3期。 PF-07220060 是一种新型、强效、口服、选择性 CDK4 抑制剂，显著减少对 CDK6 的抑制。在2024年欧洲肿瘤内科学会（ESMO）的乳腺癌大会上公布的1/2期试验（NCT04557449）的最新数据显示，此前对CDK4/6抑制剂耐药进展的乳腺癌患者，PF-07220060联合内分泌治疗完全缓解率（CR）为3%，部分缓解率（PR）为21.2%，疾病控制率(DCR)为81.8%，平均无进展生存期为8.1个月。国内目前恒瑞和百济（从昂胜医药引进）的CDK4抑制剂也已经处于临床1期开发阶段。百济这边打着BIC的口号，13.3亿美元的大手笔不知道最后能不能惊艳众人。在临床前阶段，BGB-43395已展现出比辉瑞的PF-07220060更强的抑制作用和选择性。且在GLP TOX研究中BGB-43395耐受性良好，未发生中性粒细胞减少症或肠胃毒性问题，展现了BIC的潜力。 CDK2/4/6抑制剂: 辉瑞、Nuvation Bio折戟，正大天晴NDA 2021年，Cancer cell发表的一篇研究文章，通过CRISPR方法筛选发现，CDK4/6抑制剂抵抗涉及的关键通路是cyclin E-CDK2和Myc信号通路的激活。该发现直接指导了CDK2/4/6抑制剂的研发，结果发现这种对CDK4/6抑制剂耐药的肿瘤模型仍然有显著的治疗效果。在CDK2/4/6抑制剂的研发中，辉瑞应是走在最前端，于2018年2月就已经启动了CDK2/4/6 抑制剂PF-06873600药物的1/2a 期临床，但最终还是停止该药物研发，具体原因暂未公布。无独有偶，2022年8月，Nuvation Bio宣布停止此前被广泛看好的CDK2/4/6抑制剂NUV-422的临床开发。NUV-422具备很强的血脑屏障渗透能力，因此在各类癌症以及颅内病灶的治疗中拥有良好的潜力。2021年12月，FDA授予新型CDK2/4/6抑制剂NUV-422快速通道资格认定，用于治疗高级别胶质瘤，包括多形性胶质母细胞瘤。然而，由于临床试验多名患者出现葡萄膜炎，FDA暂停部分临床试验，公司内部风险收益分析后，决定停止CDK2/4/6抑制剂NUV-422的临床开发。其最主要的原因是，与NUV-422相关的葡萄膜炎的病因尚不清楚，并且其发展似乎不可预测，如果没有大量的进一步研究，难以制定有效的缓解计划。无独有偶，辉瑞于2022年11月也停止了CDK2/4/6抑制剂PF-06873600药物的临床研究。在CDK2/4/6抑制剂的研发中，辉瑞应是走在最前端，于2018年2月就已经启动了CDK2/4/6 抑制剂PF-06873600药物的1/2a 期临床，但最终还是停止该药物研发，具体原因暂未公布。辉瑞和Nuvation Bio的先后折戟，丝毫没有影响国内药企的开发热情，仍有不少药企"头铁"地布局了CDK2/4/6抑制剂。比如正大天晴、石药集团、同源康、先声药业、锐格医药等，其中正大天晴的库莫西利的开发进度可谓遥遥领先，已经提交NDA，其他同类产品尚处于早期临床阶段。库莫西利是一种新型周期蛋白依赖性激酶2、4和6（CDK2/4/6）抑制剂，对CDK2、CDK4、CDK6激酶有不同程度的抑制效果，并且对CDK4激酶具有较强的抑制能力。研究结果显示，与阿贝西利相比，库莫西利对CDK2的抑制作用进一步提升，其增强的CDK2和CDK4抑制活性可能有助于在临床上克服目前CDK4/6抑制剂的耐药性问题。今年 7 月，CDE 已受理库莫西利联合氟维司群用于既往内分泌经治的 HR+/HER2-局部晚期或转移性乳腺癌适应症的上市申请。参考来源： 1. Xu Z, Liu Y, Song B, et al. Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor. Bioorganic & Medicinal Chemistry Letters 2024; 107. 2. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2024; 74(3): 229-63. END END END END 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

并购临床1期申请上市