更新于：2024-05-01

Hec1

NDC80 kinetochore complex component

更新于：2024-05-01

基本信息

别名

HEC、HEC1、Highly expressed in cancer protein

+ [10]

简介

Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:9315664, PubMed:12351790, PubMed:14654001, PubMed:14699129, PubMed:15062103, PubMed:15235793, PubMed:15239953, PubMed:15548592, PubMed:16732327, PubMed:30409912). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:15548592, PubMed:30409912). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020). Plays a role in chromosome congression and is essential for the end-on attachment of the kinetochores to spindle microtubules (PubMed:25743205, PubMed:23891108).

关联

项与 Hec1 相关的药物

T-1101

靶点

Hec1 x NEK2

作用机制

Hec1抑制剂 [+1]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

VTT-006

靶点-

作用机制

Hec1抑制剂

在研机构-

原研机构-

在研适应症

肿瘤

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

TAI-1

靶点-

作用机制

Hec1抑制剂

在研机构

泰纬生命科技股份有限公司

原研机构

泰纬生命科技股份有限公司

在研适应症

肿瘤

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 Hec1 相关的临床试验

NCT04685473 / Active, not recruiting临床1期

A Phase I Study of Safety, Tolerability and Pharmacokinetics of T-1101 (Tosylate) Capsules in Subjects With Advanced Refractory Solid Tumors

T-1101 (Tosylate) is a new small molecule chemical entity being developed as a potential anti-cancer therapeutic by Taivex Therapeutics Corp. T-1101 (Tosylate) is a potent anti-cancer agent in numerous human cancer cell lines. In addition, oral administration of T-1101 (Tosylate) showed tumor growth inhibition in different mouse xenograft models of human cancers. In this study, safety, tolerability and pharmacokinetic (PK) of T-1101 (Tosylate) capsules will be evaluated and also the recommended dose and regimen(s) to initiate Phase 2 will be determined.

开始日期2021-01-07

申办/合作机构

泰纬生命科技股份有限公司

NCT03349073 / Completed临床1期

An Extension Study of T-1101 (Tosylate) Administered Orally to Patients With Advanced Refractory Solid Tumors

T-1101 is a novel anti-cancer agent being developed by Taivex Therapeutics Corporation, and is being studied in a phase I dose escalation trial, protocol TAI-001. That trial's primary aim is to study the safety and tolerability of T-1101 (Tosylate) in subjects with advanced refractory solid tumors, and provides for a maximum of 2 cycles of treatment. At the end of 2 cycles of treatment, it is likely that some patients will be continuing to receive clinical benefit from T-1101 (Tosylate). The intention of this program is to enable these patients to continue to receive T-1101 (Tosylate) at the discretion of the principal investigators and Taivex Therapeutics Corporation.

开始日期2017-09-14

申办/合作机构

泰纬生命科技股份有限公司

NCT03195764 / Terminated临床1期

A Phase I Safety and Tolerability Study of T-1101 (Tosylate) as a Oral Powder for Constitution (OPC) in Patients With Advanced Refractory Solid Tumors

T-1101 (Tosylate) is a new small molecule chemical entity being developed as a potential anti-cancer therapeutic by Taivex Therapeutics Corp. T-1101 (Tosylate) is a potent anti-cancer agent in numerous human cancer cell lines. In addition, oral administration of T-1101 (Tosylate) showed tumor growth inhibition in different mouse xenograft models of human cancers. In this study, safety, tolerability and PK of T-1101 (Tosylate) will be evaluated and also the recommended dose and regimen(s) to initiate Phase 2 will be determined.

开始日期2017-09-14

申办/合作机构

泰纬生命科技股份有限公司

100 项与 Hec1 相关的临床结果

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100 项与 Hec1 相关的转化医学

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0 项与 Hec1 相关的专利（医药）

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784

项与 Hec1 相关的文献（医药）

2024-02-07·Molecular cancer research : MCR

Co-regulation of NDC80 complex subunits determines the fidelity of the spindle-assembly checkpoint and mitosis.

Article

作者: Se Hong Kim ; Thomas T Y Lau ; Man Kit Liao ; Hoi Tang Ma ; Randy Y C Poon

NDC80 complex (NDC80C) is composed of four subunits (SPC24, SPC25, NDC80, and NUF2) and is vital for kinetochore-microtubule (KT-MT) attachment during mitosis. Paradoxically, NDC80C also functions in the activation of the spindle-assembly checkpoint (SAC). This raises an interesting question regarding how mitosis is regulated when NDC80C levels are compromised. Using a degron-mediated depletion system, we found that acute silencing of SPC24 triggered a transient mitotic arrest followed by mitotic slippage. SPC24-deficient cells were unable to sustain SAC activation despite the loss of KT-MT interaction. Intriguingly, our results revealed that other subunits of the NDC80C were co-downregulated with SPC24 at a post-translational level. Silencing any individual subunit of NDC80C likewise reduced expression of the entire complex. We found that SPC24-SPC25 and NDC80-NUF2 subcomplexes could be individually stabilized using ectopically expressed subunits. Synergism of SPC24 downregulation with drugs that promote either mitotic arrest or mitotic slippage further underscored the dual roles of NDC80C in KT-MT interaction and SAC maintenance. The tight coordinated regulation of NDC80C subunits suggests that targeting individual subunit could disrupt mitotic progression and provide new avenues for therapeutic intervention. Implications: These results highlight the tight coordinated regulation of NDC80C subunits and their potential as targets for antimitotic therapies.

2024-02-02·Biochemical Society transactions

Kinetochore-microtubule error correction for biorientation: lessons from yeast.

Review

作者: Shuyu Li ; Taciana Kasciukovic ; Tomoyuki U Tanaka

Accurate chromosome segregation in mitosis relies on sister kinetochores forming stable attachments to microtubules (MTs) extending from opposite spindle poles and establishing biorientation. To achieve this, erroneous kinetochore-MT interactions must be resolved through a process called error correction, which dissolves improper kinetochore-MT attachment and allows new interactions until biorientation is achieved. The Aurora B kinase plays key roles in driving error correction by phosphorylating Dam1 and Ndc80 complexes, while Mps1 kinase, Stu2 MT polymerase and phosphatases also regulate this process. Once biorientation is formed, tension is applied to kinetochore-MT interaction, stabilizing it. In this review article, we discuss the mechanisms of kinetochore-MT interaction, error correction and biorientation. We focus mainly on recent insights from budding yeast, where the attachment of a single MT to a single kinetochore during biorientation simplifies the analysis of error correction mechanisms.

2024-01-03·bioRxiv : the preprint server for biology

SAXS/MC studies of the mixed-folded protein Cdt1 reveal monomeric, folded over conformations.

作者: Kyle P Smith ; Srinivas Chakravarthy ; Amit Rahi ; Manas Chakraborty ; Kristen M Vosberg ; Marco Tonelli ; Maximilian G Plach ; Arabela A Grigorescu ; Joseph E Curtis ; Dileep Varma

Cdt1 is a protein critical for DNA replication licensing and is well-established to be a binding partner of the minichromosome maintenance (MCM) complex. Cdt1 has also been demonstrated to have an emerging, "moonlighting" role at the kinetochore via direct binding to microtubules and to the Ndc80 complex. However, it is not known how the structure and conformations of Cdt1 could allow for these multiple, completely unique sets of protein complexes. And while there exist multiple robust methods to study entirely folded or entirely unfolded proteins, structure-function studies of combined, mixed folded/disordered proteins remain challenging. It this work, we employ multiple orthogonal biophysical and computational techniques to provide a detailed structural characterization of human Cdt1 92-546. DSF and DSCD show both folded winged helix (WH) domains of Cdt1 are relatively unstable. CD and NMR show the N-terminal and the linker regions are intrinsically disordered. Using DLS and SEC-MALS, we show that Cdt1 is polydisperse, monomeric at high concentrations, and without any apparent inter-molecular self-association. SEC-SAXS of the monomer in solution enabled computational modeling of the protein in silico . Using the program SASSIE, we performed rigid body Monte Carlo simulations to generate a conformational ensemble. Using experimental SAXS data, we filtered for conformations which did and did not fit our data. We observe that neither fully extended nor extremely compact Cdt1 conformations are consistent with our SAXS data. The best fit models have the N-terminal and linker regions extended into solution and the two folded domains close to each other in apparent "folded over" conformations. The best fit Cdt1 conformations are consistent with a function as a scaffold protein which may be sterically blocked without the presence of binding partners. Our studies also provide a template for combining experimental and computational biophysical techniques to study mixed-folded proteins.

项与 Hec1 相关的新闻（医药）

2023-11-05

·生物探索

Cell Discovery | 人类卵子非整倍体高发生率的潜在机理

非整倍体严重损害女性生育能力，增加出生缺陷的发生率。即使是来自年轻女性的人类卵子的非整倍体率也明显高于其他哺乳动物。然而，人类卵子非整倍体高发生率的内在遗传因素在很大程度上仍然未知。2023年10月24日，复旦大学王磊、武田宇及桑庆共同通讯在Cell Discovery（IF=34）在线发表题为“Ectopic expression of human TUBB8 leads to increased aneuploidy in mouse oocytes”的研究论文，该研究发现人类TUBB8 在小鼠卵母细胞中的异位表达通过引起着丝点微管(K-MT)附着缺陷增加了非整倍体的发生率。在表达TUBB8的小鼠卵母细胞中，拉伸的二价体受到的张力较小，导致在I中期后期，AURKB/C对HEC1的持续磷酸化状态损害了已建立的正确的K-MT附着。该研究发现，没有C端尾的TUBB8异位表达通过减少错误的K-MT附着而降低了非整倍体率。重要的是，在复发性流产患者中发现了TUBB8 C端尾部的变异。小鼠卵母细胞中TUBB8变体的异位表达也会损害K-MT附着并增加非整倍体率。总之，该研究为人类卵子非整倍体的生理机制以及反复流产的病理生理机制提供了新的认识。人类卵子经常含有不正确数量的染色体，这种情况被称为非整倍体，它是女性不育/生育能力低下、反复流产和出生缺陷的主要原因之一。20 ~ 32岁女性非整倍体卵的发生率为20% ~ 30%，高于许多其他生殖年龄物种，如小鼠(1% ~ 4%)、猪(3% ~ 10%)、牛(5.8% ~ 7.1%)、马(~15.6%)和恒河猴(7.1% ~ 18.4%)。虽然在人类卵子中观察到高频率的非整倍体，但在生理条件下导致人类卵子高频率非整倍体的具体遗传因素和确切机制仍有待阐明。人类卵子的非整倍性是由减数分裂I中染色体分离错误引起的。研究表明，瞬态三极纺锤体诱导的三向分裂可能导致后期染色体分离容易出错。人类卵母细胞中缺乏KIFC1被认为是其不稳定和多纺锤极的原因，导致非整倍性增加。此外，短暂的不稳定多极纺锤体会导致人类卵母细胞中异常的着丝点微管(K-MT)附着，从而导致染色体误分离。成对的着丝点由来自相对纺锤极的微管连接，以确保准确的染色体分离。稳定的着丝点微管(也称为k-纤维)是正确的K-MT附着所必需的。TUBB8的异位表达增加了小鼠卵母细胞非整倍体的发生率（图源自Cell Discovery ）微管通常由保守的α和β-微管蛋白异二聚体组成。人β-微管蛋白由9个同型组成，包括TUBB1、TUBB2A、TUBB2B、TUBB3、TUBB4A、TUBB4B、TUBB5、TUBB6和TUBB8。除TUBB8外，在小鼠卵母细胞中也检测到8种。之前证明了TUBB8在人类卵母细胞纺锤体中是唯一表达的，纺锤体由含有显性β-微管蛋白同型编码的TUBB821的异源二聚体聚合而成。而小鼠卵母细胞纺锤体主要由β-微管蛋白同型组成，如TUBB3、TUBB4B、TUBB5和TUBB6。此外，之前的研究表明，TUBB8变异患者表现出由广泛的纺锤体缺陷引起的卵母细胞减数分裂停滞、早期胚胎发育停滞或非整倍体。该研究证明了灵长类特异性TUBB8的异位表达诱导小鼠卵母细胞非整倍体的升级，并进一步阐明了TUBB8诱导非整倍体的机制。此外，研究发现TUBB8 C端尾部的变异更容易产生非整倍体卵子，并与复发性流产有关。这些结果为人类卵子高频率非整倍体的生理和病理生理机制提供了新的认识。文章来源“iNature”责编|探索君排版|探索君参考文献：Dong, J., Jin, L., Bao, S. et al. Ectopic expression of human TUBB8 leads to increased aneuploidy in mouse oocytes. Cell Discov 9, 105 (2023). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41421-023-00599-zEnd往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

临床1期临床结果

2022-06-06

·BioSpace

Eureka Therapeutics Announces Publication of Study Demonstrating Broad Anti-Tumor Activity of TCR Mimic-Redirected T Cells Targeting NDC80

June 6, 2022 12:05 UTC EMERYVILLE, Calif.--(BUSINESS WIRE)-- Eureka Therapeutics, Inc., a clinical-stage biotechnology company developing novel T cell therapies to treat solid tumors, today announced the publication of a preclinical study in blood entitled “A TCR Mimic CAR T Cell Specific for NDC80 Is Broadly Reactive With Solid Tumors and Hematological Malignancies”. The study was led by Dr. Cheng Liu, President & Chief Executive Officer of Eureka and Dr. Martin Klatt and Dr. David Scheinberg of Memorial Sloan Kettering Cancer Center (MSK). Chimeric antigen receptor (CAR) T cells represent a novel class of FDA-approved drugs with high efficacy against refractory B cell-derived malignancies. However, target identification and selection for CAR T cell therapy remains challenging as most cell surface proteins are not cancer-specific and therefore often not adaptable for CAR T cell therapy. In contrast, many intracellular proteins are highly tumor-specific and targetable after being presented on the cell surface by human leukocyte antigen (HLA) complexes in the form of peptide-MHC complexes. T cell receptor mimic (TCRm) antibodies can recognize peptide-MHC complexes similarly to TCRs, but with the versatility and applicability of an antibody. In collaboration with MSK, Eureka scientists used its E-ALPHA® platform to identify TCRm antibodies that target the NDC80-derived complex. NDC80 is an intracellular protein over-expressed in multiple tumor types such as ALL, AML, lymphoma, melanoma, mesothelioma, pancreatic and thyroid cancer. In the study, anti-NDC80 TCRm-redirected T cells demonstrated high specificity in recognizing and killing multiple cancer cell lines. Moreover, no toxicities to healthy leukocytes and hematopoietic stem cells were observed. “TCR mimic antibodies can unlock the potential of T-cell therapies by targeting intracellular proteins that are presently not druggable by conventional antibodies or conventional CAR-T cells that target cell surface proteins,” said Dr. Cheng Liu, Founder and CEO, Eureka Therapeutics. “We are excited by the study and look forward to seeing the expanded use of TCR mimic antibodies in other cancer types.” About Eureka Therapeutics Eureka Therapeutics, Inc. is a privately-held clinical-stage biotechnology company focusing on developing novel T cell therapies to treat cancers. Its core technology centers around its proprietary ARTEMIS® cell receptor platform and E-ALPHA® antibody discovery platform for the discovery and development of potentially safer and more effective T cell therapies for the treatment of solid tumors and hematologic malignancies. The Company currently has two clinical programs, ET140203 (ARYA1 and ARYA2) and ECT204 (ARYA3), in Phase I/II US trials in patients with advanced liver cancer. Eureka Therapeutics, Inc. is headquartered in the San Francisco Bay Area. For more information on Eureka, please visit .

抗体细胞疗法