更新于：2024-11-01

TTBK2

更新于：2024-11-01

基本信息

别名

KIAA0847、SCA11、spinocerebellar ataxia 11

+ [3]

简介

Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to the recruitment of IFT proteins, which build the ciliary axoneme. Has some substrate preference for proteins that are already phosphorylated on a Tyr residue at the +2 position relative to the phosphorylation site. Able to phosphorylate tau on serines in vitro (PubMed:23141541). Phosphorylates MPHOSPH9 which promotes its ubiquitination and proteasomal degradation, loss of MPHOSPH9 facilitates the removal of the CP110-CEP97 complex (a negative regulator of ciliogenesis) from the mother centrioles, promoting the initiation of ciliogenesis (PubMed:30375385).

关联

项与 TTBK2 相关的药物

WO2023206609

专利挖掘

靶点

TTBK2

作用机制-

在研机构

厦门大学

原研机构

厦门大学

在研适应症

神经系统疾病

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TTBK2 相关的临床结果

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100 项与 TTBK2 相关的转化医学

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0 项与 TTBK2 相关的专利（医药）

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102

项与 TTBK2 相关的文献（医药）

2024-10-03·Translational Neuroscience

TTBK2 ^T3290C mutation in spinocerebellar ataxia 11 interferes with ciliogenesis

Article

作者: Luo, Ruiqing ; Li, Ping ; Hu, Shuai ; Qi, Xueliang ; Zeng, Xiaoxia

AbstractThis study aimed to elucidate the impact of the TTBK2T3290C mutation (MUT) associated with Spinocerebellar Ataxia 11 (SCA11) on TTBK2 expression, function, and ciliogenesis. Lymphocytes were isolated from peripheral blood samples of SCA11 family members with the MUT and healthy controls (wild-type, WT). HEK-293 cells transfected with either WT or MUT TTBK2 plasmids were used to assess the MUT’s impact on TTBK2 protein expression, enzymatic activity, and its binding to Cep164 protein. Mouse embryonic fibroblast cells transfected with WT or MUT TTBK2 plasmids examined the MUT’s effect on cilia formation. Clinically, there was no significant difference in the expression of TTBK2 between the SCA11 patients and healthy individuals. The TTBK2T3290C MUT did not affect protein expression or enzymatic activity but did reduce ciliary formation in embryonic cells and decreased binding affinity to Cep164. Therefore, our data suggested that the TTBK2T3290C MUT in SCA11 may impair ciliogenesis by weakening the interaction with Cep164.

2024-10-01·Cell Death & Differentiation

Regulation of primary cilia disassembly through HUWE1-mediated TTBK2 degradation plays a crucial role in cerebellar development and medulloblastoma growth

Article

作者: Kao, Chien-Han ; Ayrault, Olivier ; Chang, Chia-Hsiang ; Wang, Won-Jing ; Lin, Pei-Yi ; Tsai, Jin-Wu ; Cheng, Yu-Wen ; Hsu, Chih-Sin ; Chung, Bon-Chu ; Su, Ting-Yu ; Li, Yue-Ru ; Wang, Yu-Ting ; Lin, I-Hsuan ; Tung, Chien-Yi ; Hsu, Pang-Hung ; Tsai, Yu-Shuen

AbstractDevelopment of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.

2023-04-14·Scientific reports

Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis.

Article

作者: Axtman, Alison D ; Beltran, Adriana S ; Drewry, David H ; Beltran, Alvaro A ; Dunn, Andrea S ; Marquez, Ariana B ; Howell, Stefanie ; Smith, Jeffery L ; Bashore, Frances M ; Chaikuad, Apirat

Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact of TTBK1 inhibition in diseases like Alzheimer's disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 knockout in iPSCs, confirming a role for TTBK2 in ciliogenesis.

项与 TTBK2 相关的新闻（医药）

2024-02-29

·PRNewswire

BioArctic: Latest data on lecanemab to be presented at the 2024 AD/PD™ congress

STOCKHOLM, Feb. 29, 2024 /PRNewswire/ -- BioArctic AB (publ) (STO: BIOA-B) today announced that the company and its partner Eisai will present new data on lecanemab (brand name: Leqembi®) at the 2024 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD™), to be held in Lisbon, Portugal and virtually, March 5-9. In total, lecanemab will be featured in six presentations, including an oral presentation by BioArctic's founder Professor Lars Lannfelt. Lecanemab is the result of a long-standing collaboration between BioArctic and Eisai, and the anti-amyloid beta (Aβ) protofibril antibody was originally developed by BioArctic based on the work of Professor Lars Lannfelt and his discovery of the Arctic mutation in Alzheimer's disease. At AD/PD, BioArctic will present one oral presentation and one poster on lecanemab, both focused on the binding properties of lecanemab to various types of Aβ of lecanemab compared to several other Aβ antibodies. The company will also have two other posters related to Alzheimer's disease. In addition to BioArctic's presentations, Eisai will present four oral presentations on lecanemab results. From the Phase 3 Clarity AD study in early Alzheimer's disease[1] with confirmed brain Aβ accumulation, data will include the effect of lecanemab treatment on tau[2] accumulation in whole brain regions, and outcomes of long-term efficacy of lecanemab. In addition, the differences in the binding properties of multiple anti-amyloid (Aβ) antibodies to various types of Aβ and other data will be presented. Eisai will also sponsor a symposium featuring three prominent clinical experts in the field of Alzheimer's disease, Dr. Jeffrey Cummings, Dr. Robert Perneczky and Dr. Miia Kivipelto. Dr. Jeffrey Cummings will chair the symposium, and provide an overview of meaningful benefits, including clinical meaningfulness and the evolution of approaches for the clinical study of Alzheimer's disease. Dr. Robert Perneczky will discuss how to assess meaningful benefits of treatments in development for Alzheimer's disease. Dr. Miia Kivipelto's presentation will provide new statistical methods to measure meaningful benefits and address various stakeholder perspectives. Furthermore, Eisai's Chief Clinical Officer, Lynn Kramer, M.D., will give a plenary presentation titled "Novel approaches to clinical development and the future potential of simulated placebo" on March 7 at the "Aβ TARGETING THERAPIES IN AD 1" session. Eisai serves as the lead of Leqembi development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority. BioArctic has the right to commercialize lecanemab in the Nordic region, pending European approval, and currently Eisai and BioArctic are preparing for a joint commercialization in the region. Presentations by BioArctic and Eisai Oral presentations Poster presentations Eisai-Sponsored Symposium Plenary presentation This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such investigational agents will successfully complete clinical development or gain health authority approval. The information was released for public disclosure, through the agency of the contact persons below, on February 29, 2024, at 08.00 a.m. CET. For further information, please contact: Oskar Bosson, VP Communications and IR E-mail: [email protected] Phone: +46 70 410 71 80 Jiang Millington, Director Corporate Communication and Social Media E-mail: [email protected] Phone: +46 79 33 99 166 About lecanemab (generic name, U.S., Japan and China brand name: Leqembi®) Lecanemab is the result of a strategic research alliance between BioArctic and Eisai. Lecanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril) and insoluble forms of amyloid-beta (Aβ). In the U.S., Leqembi was granted traditional approval by the US Food and Drug Administration (FDA) on July 6, 2023. Leqembi is indicated as a disease-modifying treatment for Alzheimer's disease (AD) in the US. Treatment with Leqembi should be initiated in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. Please see full U.S. Prescribing Information. In Japan, Eisai received approval from the Ministry of Health, Labour and Welfare (MHLW) on September 25, 2023, to manufacture and market lecanemab as a treatment for slowing progression of MCI and mild dementia due to AD. Furthermore, in China, Leqembi was approved by the National Medical Products Administration (NMPA) as a treatment of MCI due to AD and mild AD dementia in January 2024. Eisai has also submitted applications for approval of lecanemab in 14 different countries, including EU, Canada and Great Britain. Eisai has completed a lecanemab subcutaneous bioavailability study, and subcutaneous dosing is currently being evaluated in the Clarity AD (Study 301) open-label extension (OLE) study. A maintenance dosing regimen has been evaluated as part of the Phase 2b study (Study 201). Since July 2020 Eisai's Phase 3 clinical study (AHEAD 3-45) for individuals with preclinical AD, meaning they are clinically normal and have intermediate or elevated levels of amyloid in their brains, is ongoing. AHEAD 3-45 is conducted as a public-private partnership between the Alzheimer's Clinical Trial Consortium that provides the infrastructure for academic clinical trials in AD and related dementias in the U.S, funded by the National Institute on Aging, part of the National Institutes of Health and Eisai. Since January 2022, the Tau NexGen clinical study for Dominantly Inherited AD (DIAD), that is conducted by Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by Washington University School of Medicine in St. Louis, is ongoing and includes lecanemab as the backbone anti-amyloid therapy. About the collaboration between BioArctic and Eisai Since 2005, BioArctic has a long-term collaboration with Eisai regarding the development and commercialization of drugs for the treatment of Alzheimer's disease. The most important agreements are the Development and Commercialization Agreement for the lecanemab antibody, which was signed 2007, and the Development and Commercialization agreement for the antibody Leqembi back-up for Alzheimer's disease, which was signed 2015. In 2014, Eisai and Biogen entered into a joint development and commercialization agreement for lecanemab. Eisai is responsible for the clinical development, application for market approval and commercialization of the products for Alzheimer's disease. BioArctic has the right to commercialize lecanemab in the Nordic region under certain conditions and is currently preparing for commercialization in the Nordics together with Eisai. BioArctic has no development costs for lecanemab in Alzheimer's disease and is entitled to payments in connection with regulatory approvals, and sales milestones as well as royalties on global sales. About BioArctic AB BioArctic AB (publ) is a Swedish research-based biopharma company focusing on innovative treatments that can delay or stop the progression of neurodegenerative diseases. The company invented Leqembi® (lecanemab) – the world's first drug proven to slow the progression of the disease and reduce cognitive impairment in early Alzheimer's disease. Leqembi has been developed together with BioArctic's partner Eisai, who are responsible for regulatory interactions and commercialization globally. In addition to Leqembi, BioArctic has a broad research portfolio with antibodies against Parkinson's disease and ALS as well as additional projects against Alzheimer's disease. Several of the projects utilize the company's proprietary BrainTransporter™ technology, which has the potential to actively transport antibodies across the blood-brain barrier to enhance the efficacy of the treatment. BioArctic's B share (BIOA B) is listed on Nasdaq Stockholm Large Cap. For further information, please visit . [1] Early Alzheimer's disease includes mild cognitive impairment (MCI) due to Alzheimer's disease and mild Alzheimer's disease [2] A protein that aggregates intracellularly in nerve cells in Alzheimer's disease, disrupting both the function and survival of the cell. Tau levels can be measured in plasma, cerebrospinal fluid, and with a positron camera (PET). The following files are available for download:

上市批准临床3期临床2期引进/卖出