更新于：2024-05-01

CK1δ

casein kinase 1 delta

更新于：2024-05-01

基本信息

别名

casein kinase 1 delta、casein kinase 1, delta、Casein kinase I isoform delta

+ [6]

简介

Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In balance with PP1, determines the circadian period length through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. Phosphorylates NEDD9/HEF1 (By similarity). EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.

关联

项与 CK1δ 相关的药物

CK1δ inhibitors(Janssen)

靶点-

作用机制

CK1δ抑制剂

在研机构

Janssen Pharmaceuticals, Inc.

原研机构

Janssen Pharmaceuticals, Inc.

在研适应症

睡眠异常

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

NMRA-CK1δ

靶点

CK1δ

作用机制

CK1δ抑制剂

在研机构

Neumora Therapeutics, Inc.

原研机构

Neumora Therapeutics, Inc.

在研适应症

阿尔茨海默症 [+2]

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

CK1 delta/epsilon inhibitors (Pfizer)

靶点

CK1δ x CK1ε

作用机制

CK1δ抑制剂 [+1]

在研机构

Pfizer Inc.

原研机构

Pfizer Inc.

在研适应症

行为障碍 [+3]

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

100 项与 CK1δ 相关的临床结果

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100 项与 CK1δ 相关的转化医学

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0 项与 CK1δ 相关的专利（医药）

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336

项与 CK1δ 相关的文献（医药）

2024-02-01·Cellular and molecular life sciences : CMLS

Combinatorial regulation by ERK1/2 and CK1δ protein kinases leads to HIF-1α association with microtubules and facilitates its symmetrical distribution during mitosis.

Article

作者: Christina Arseni ; Martina Samiotaki ; George Panayotou ; George Simos ; Ilias Mylonis

Hypoxia-inducible factor-1 (HIF-1) is the key transcriptional mediator of the cellular response to hypoxia and is also involved in cancer progression. Regulation of its oxygen-sensitive HIF-1α subunit involves post-translational modifications that control its stability, subcellular localization, and activity. We have previously reported that phosphorylation of the HIF-1α C-terminal domain by ERK1/2 promotes HIF-1α nuclear accumulation and stimulates HIF-1 activity while lack of this modification triggers HIF-1α nuclear export and its association with mitochondria. On the other hand, modification of the N-terminal domain of HIF-1α by CK1δ impairs HIF-1 activity by obstructing the formation of a HIF-1α/ARNT heterodimer. Investigation of these two antagonistic events by expressing double phospho-site mutants in HIF1A^-/- cells under hypoxia revealed independent and additive phosphorylation effects that can create a gradient of HIF-1α subcellular localization and transcriptional activity. Furthermore, modification by CK1δ caused mitochondrial release of the non-nuclear HIF-1α form and binding to microtubules via its N-terminal domain. In agreement, endogenous HIF-1α could be shown to co-localize with mitotic spindle microtubules and interact with tubulin, both of which were inhibited by CK1δ silencing or inhibition. Moreover, CK1δ expression was necessary for equal partitioning of mother cell-produced HIF-1α to the daughter cell nuclei at the end of mitosis. Overall, our results suggest that phosphorylation by CK1δ stimulates the association of non-nuclear HIF-1α with microtubules, which may serve as a means to establish a symmetric distribution of HIF-1α during cell division under low oxygen conditions.

2024-01-06·Translational oncology

CK1δ/ε inhibition induces ULK1-mediated autophagy in tumorigenesis.

Article

作者: Vivian Weiwen Xue ; Shanshan Liu ; Qi Sun ; Jiong Ning ; Huan Li ; Weilan Wang ; Sapna Sayed ; Xibao Zhao ; Li Fu ; Desheng Lu

INTRODUCTION:

Autophagy is an important mechanism of cell homeostasis maintenance. As essential serine/threonine-protein kinases, casein kinase I family members affect tumorigenesis by regulating a variety of cellular progression. However, the mechanism by which they regulate autophagy remains unclear.

MATERIALS AND METHODS:

We silenced CK1δ/ε in cancer cells and observed cell morphology, the expression of autophagy-related genes, and its impact on cancer cell growth and viability. By inhibiting CK1δ/ε-induced upregulation of autophagy genes, we profiled the regulatory mechanism of CK1δ/ε on autophagy and cancer cell growth. The impact of CK1δ/ε inhibition on tumor cell growth was also assessed in vivo.

RESULTS:

Here, we found that CK1δ/ε played an important role in ULK1-mediated autophagy regulation in both lung cancer and melanoma cells. Mechanically, silencing CK1δ/ε increased ULK1 expression with enhanced autophagic flux and suppressed cancer cell proliferation, while ULK1 knockdown blocked the activation of autophagy caused by CK1δ/ε inhibition. By silencing CK1δ/ε in syngeneic mouse model bearing LLC1 murine lung cancer cells in vivo, we observed tumor growth suppression mediated by CK1δ/ε inhibition.

CONCLUSION:

Our results provide evidence for the role of CK1δ/ε in the regulation of tumorigenesis via the ULK1-mediated autophagy, and also suggest the impact of CK1δ/ε inhibition on tumor growth and its significance as a potential therapeutic target.

2023-12-02·Molecular genetics & genomic medicine

Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study.

Article

作者: Erica Rosina ; Lidia Pezzani ; Erika Apuril ; Laura Pezzoli ; Daniela Marchetti ; Matteo Bellini ; Camilla Lucca ; Camilla Meossi ; Marta Massimello ; Milena Mariani ; Agnese Scatigno ; Elisa Cattaneo ; Lorenzo Colombo ; Silvia Maitz ; Anna Cereda ; Donatella Milani ; Luigina Spaccini ; Maria Francesca Bedeschi ; Angelo Selicorni ; Maria Iascone

BACKGROUND:

The recent guidelines suggest the use of genome-wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi-step pathway, thus requiring several genetic tests to end the so-called 'diagnostic odyssey'.

METHODS:

We reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first-tier trio-WES, including exome-based copy number variation analysis, in parallel to a 'traditional approach' of two/three sequential genetic tests.

RESULTS:

First-tier trio-WES detected a conclusive diagnosis in 41.6% of patients, way above what was found with routine genetic testing (25%), with a time-to-result of about 50 days. Notably, the study showed that 44% of WES-reached diagnoses would be missed with the traditional approach. The diagnostic rate (DR) of the two approaches varied in relation to the phenotypic class of referral and to the proportion of cases with a defined diagnostic suspect, proving the major difference for neurodevelopmental disorders. Moreover, trio-WES analysis detected variants in candidate genes of unknown significance (EPHA4, DTNA, SYNCRIP, NCOR1, TFDP1, SPRED3, EDA2R, PHF12, PPP1R12A, WDR91, CDC42BPG, CSNK1D, EIF3H, TMEM63B, RIPPLY3) in 19.4% of undiagnosed cases.

CONCLUSION:

Our findings represent real-practice evidence of how first-tier genome-wide sequencing tests significantly improve the DR for paediatric outpatients with a suspected underlying genetic aetiology, thereby allowing a time-saving setting of the correct management, follow-up and family planning.

项与 CK1δ 相关的新闻（医药）

2023-03-30

·drugs

Cluster Headache, Migraine Highly Circadian

THURSDAY, March 30, 2023 -- Cluster headache and migraine are highly circadian, according to a review published online March 29 in Neurology . Barlas Benkli, M.D., from UT Health Houston, and colleagues conducted a systematic review of 72 studies to examine circadian features of cluster headache and migraine. In addition, a genetic analysis for genes with a circadian pattern of expression (clock controlled genes [CCGs]) was conducted by cross-referencing 16 genome-wide association studies of headache, one nonhuman primate study of CCGs in various tissues, and 16 imaging reviews of brain areas relevant in headache disorders. The researchers found that for cluster headache, a meta-analysis across 16 studies showed a circadian pattern of attacks in 70.5 percent of participants, with a clear circadian peak between 21.00 and 03.00, and with circannual peaks in spring and autumn. Across studies, chronotype was highly variable. Lower melatonin and higher cortisol levels were reported at the systems level. Cluster headache was associated with core circadian genes CLOCK and REV-ERB α at the cellular level; five of nine cluster headache susceptibility genes were CCGs. For migraine, 50.1 percent of participants across eight studies showed a clear circadian pattern of attacks, with a clear circadian trough between 23.00 and 07.00, and a broad circannual peak between April and October. Across studies, chronotype was highly variable. Urinary melatonin levels were lower in migraine participants at the systems level and were even lower during an attack. Migraine was associated with core circadian genes CK1δ and RORα at the cellular level; 110 of 168 migraine susceptibility genes were CCGs. "These results raise the potential for using circadian-based treatments for headache disorders," a coauthor said in a statement. One author disclosed financial ties to Lundbeck. Abstract/Full Text (subscription or payment may be required) Editorial (subscription or payment may be required) Posted March 2023

临床结果

2023-03-09

·药渡Daily

潜力新靶点系列1：CK1靶点药物研发盘点

1 前言蛋白激酶介导的蛋白质磷酸化是细胞中许多信号通路激活和失活的核心，因此，各种蛋白激酶的异常活性往往与许多疾病的发生和进展有关，特别是癌症。相应的，蛋白激酶是最具吸引力的药物抑制靶点之一，超过70种小分子激酶抑制剂已被批准用于临床[1]。在20世纪70年代初，体外酪蛋白磷酸化实验发现酪蛋白激酶1(casein kinase 1，CK1) 家族由不同的成员构成，随后CK1与不同信号分子构成的底物组合被大量发现。CK1家族广泛存在于不同的物种，从酵母到人的许多真核生物中都表达CK1家族成员且它们均具有高度保守性。哺乳动物CK1同种型 (α，β，γ，δ，ε) 及其剪接变体参与细胞不同的生理过程，包括膜运输、昼夜节律、细胞周期进程调控、染色体分离、细胞凋亡和细胞分化等，所有CK1成员的N端和C端非催化结构域显著不同，但是它们的激酶结构域具有高度的保守性。CK1在调控其他生命进程的同时其自身的活动和表达也受到严格调控，从而保证生命体各项活动有序进行。已知CK1调节的机制包括通过抑制性自磷酸化进行磷酸化和(或)被其他细胞蛋白激酶磷酸化，与细胞蛋白质或亚细胞隔离相互作用。CK1家族具有与多种底物结合的部位并且参与调节细胞生命过程，它在Wnt和Hedgehog(Hh)等信号调控、昼夜节律的调节、膜运输、细胞骨架维持、细胞分裂、DNA修复和核定位等过程中均扮演重要角色。CK1的识别基序可以在多种细胞中发现，基于细胞功能的多样性，如在免疫炎症反应和中心体相关的过程、DNA损伤相关的信号转导、昼夜节律调控中，CK1 以不同的形式调控不同的信号通路从而负责调节组织细胞的生长、增殖和凋亡等过程，因此如果CK1家族在信号通路中某一环节功能失调或障碍会导致机体病理过程的发生，如肿瘤形成或神经疾病等。图1 CK1中心体相关功能2 CK1信号通路在过去十年中出现的激酶中，酪蛋白激酶1 (CK1)已被认为是治疗包括癌症在内的多种疾病的有吸引力的靶点。个别CK1亚型显示出高度的结构同源性，这使得鉴定异构体选择性抑制剂具有挑战性，而它们涉及不同的生物过程。CK1激酶在几种细胞通信级联中起着关键作用，例如，CK1δ/ε成员在Wnt/β-catenin信号传导中起着激活作用，而CK1α则可以磷酸化β-catenin并触发其降解，充当Wnt信号通路抑制剂，另外也参与Hedgehog 及Hippo等信号通路的调控。在典型的Wnt/β-catenin信号通路中，所有CK1家族成员都参与其中。然而，这种参与是相当复杂的。在缺乏Wnt配体的情况下，CK1α与轴蛋白、腺瘤性大肠息肉病(APC)和β-catenin(Ser-45)相互作用并磷酸化，从而引发β-catenin被GSK3β进一步磷酸化并随后降解(图2A)。因此细胞质中的β-catenin含量很低，其下游的靶基因转录处于抑制状态。当Wnt配体存在时，GSK3β介导的β-catenin磷酸化被抑制，β-catenin最终不会被降解。该过程会受到CK1α，CK1γ，CK1ε和CK1δ的调节，最终导致β-catenin在细胞质中稳定存在，游离的β-catenin被转运入核，与TCF/LEF复合物等共激活因子相互作用,激活Wnt下游的靶基因转录。图2 CK1与Wnt信号通路[2]3 CK1抑制剂在研情况目前，进入临床的仅有Biotheryx Inc开发的BTX-A51及BTX-1188，且均为CK1α与其他靶点联合的药物，而CK1α也被认为是治疗急性髓系白血病(AML)的一个有吸引力的靶点。适应症方面，仅有辉瑞在开发精神疾病，其他药物均集中于肿瘤适应症的开发。全球首款PI3Kδ/CK1ε抑制剂Umbralisib（UKONIQ）是TG Therapeutics研发并于2021年2月获美国FDA批准上市，Umbralisib曾被美国FDA调查是否会增加患者死亡的风险，于2022年1月27日暂停了两项临床试验，随后被FDA撤回加速批准。4结语虽然CK1抑制剂作为药物靶标具有很大的潜力，但开发可用于体内的选择性CK1抑制剂仍然困难重重。创新药研发，每一关都是九死一生的冒险，即使成功获批上市，后续的临床应用如果出现安全性等问题，依然可能面临撤市的风险。参考文献[1] Attwood, M.M., Fabbro, D.,Sokolov, A.V. et al. Trends in kinase drug discovery: targets, indications andinhibitor design[J]. Nat Rev Drug Discov, 2021, 20, 839-861.[2] Knippschild U , Marc Krüger, Richter J , et al. The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis[J]. Frontiers in Oncology, 2014, 4(4):96.医药咨询业务介绍药渡咨询依托其强大的药学数据库资源以及多学科背景的项目团成员，为国内外医药企业、投资机构、政府和园区提供产品线规划、立项、生产、销售项目尽调、价值评估和BD等各个环节定制化解决方案。1. 为国内外企业完成200多亿的融资和并购进行了CDD和项目价值评估2. 为全球TOP10的MNC中一半以上提供产品战略和BD机会服务3. 为国内外近20家VC或PE提供技术尽职调查服务4. 为国内50多家上市药企行业研究和具体项目转让评估服务5. 为多个园区的项目落地和执行提供可行性论证服务免责声明：“药渡Daily”公众号所转载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。END👇关注药渡数据媒体矩阵

放射疗法

2021-10-13

·BioSpace

Money on the Move: October 6 – 12

Investors are dropping dollars into the life sciences industry like the trees are dropping their leaves. Here’s who’s raking in the cash this week. Neumora Therapeutics Uncloaking with a massive $500 million in financing, neuroscience-focused Neumora has hit the ground running. A strategic partnership with mega biotech Amgen will develop and commercialize assets targeting casein kinase 1 delta and glucocerebrosidase for neurodegenerative diseases. With a portfolio of eight programs in varying stages from internal discovery assets, Neumora is developing precision medicines for complex brain diseases. Paul L. Berns, cofounder, chairman and CEO said the company was founded to approach drug development in a “smarter, more precise way.” “Neumora is built at scale to pioneer potential best-in-class precision medicines for brain diseases, and we believe that integrating data sciences is the key.” Pyxis Oncology Mere months after its $152 million Series B round, this Cambridge-based company hopped on the Nasdaq’s ticker board with the symbol PYXS. Selling at $16 a share, Pyxis drew in about $168 million in its IPO last week. The biotech develops ADCs and monoclonal antibodies targeting different forms of cancer. Most of the funds are earmarked for Pyxis’ three lead ADC programs, taking the candidates through preclinical research, NDA and Phase I trials. CinCor Pharma Cincinnati’s CinCor just finished its $143 million Series B financing round to support the development of its lead drug for hypertension, primary aldosteronism and chronic kidney disease. CIN-107 is an oral small molecule that inhibits aldosterone synthase. The funds will be used to complete ongoing Phase II trials for patients with resistant hypertension and hypertensive patients with primary aldosteronism. The round will also fuel two new Phase II trials in patients with uncontrolled hypertension and to study the drugs impact on blood pressure and kidney function in CKD patients. Twin Health AI drives the future of medical devices and services, treating and preventing disease through technology. Last week, Twin Health scooped up a $140 million Series C to scale services of its Whole Body Digital Twin. The precision health service builds a dynamic representation of each patient’s unique metabolism through non-invasive wearable sensors and patient tracking to help reverse and prevent chronic metabolic diseases. With the idea that your body can “heal itself,” the program provides real-time health insights with recommendations to address the root cause of chronic metabolic diseases like type 2 diabetes. In a randomized controlled trial, over 90% of patients achieved type 2 diabetes reversal with 92% able to eliminate all diabetes drugs. Isoplexis With stock listed at $15 a share, IsoPlexis scored $125 million from its IPO. Developing tech to support drug R&D is the company’s focus. Its commercialized technology platform, based on tech licensed from Yale, assists biopharma companies in analyzing proteins. Initially focused on applications for cancer immunology and cell and gene therapies, IsoPlexis is expanding its scope to include infectious and neurologic disease as well as inflammatory conditions. Proceeds will be used for general corporate purposes. Intergalactic Therapeutics Launching off with $75 million in seed funding, Intergalactic is one of the handful of biotech companies aiming to create non-viral gene therapies. Currently approved gene therapies rely on viruses to deliver the DNA strands. While effective, viruses can cause safety concerns and limit treatments to one-time use. Intergalactic is relying on technique with 40 years of research behind it, electroporation, which uses electrical fields to open doorways into cells. Like many gene editing companies, this one will start by targeting diseases affecting the eye, as well as respiratory disease and cancer. The goal is for in-human trials within two years. Cognition Therapeutics Since Biogen’s landmark approval of Aduhelm, the industry is seeing a fresh surge of interest in targeting amyloid proteins to treat the devastating disease of Alzheimer’s. Cognition is developing small molecules to break up amyloid in the brain with its lead drug. By jumping on the Nasdaq, the company now has a fresh $45.2 million to push forward CT1812 to Phase II testing in patients with mild-to-moderate Alzheimer’s. A second candidate is targeting wet form of age-related macular degeneration. $16.2 million of the IPO raise will funnel into that program’s Phase II. Chance Pharmaceuticals Out of Hangzhou, China, Chance has the “leading particle engineering knowhow” for developing inhaled therapeutics for today’s debilitating diseases. With seven products in the early stages of its pipeline, the company lists its R&D as including diseases like chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, and central nervous system disorders. This week Chance scored $30 million in Series C financing to advance the pipeline, initiate collaborations and accelerate construction on a manufacturing facility.

抗体小分子药物合作IPO抗体药物偶联物