更新于：2024-11-01

Ku70/80

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 Ku70/80 相关的药物

VIO-01

靶点

Ku70/80 x MRN x PARP1

作用机制

Ku70/80 抑制剂 [+2]

在研机构

Valerio Therapeutics SA

原研机构

Valerio Therapeutics SA

在研适应症

乳腺癌 [+3]

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 Ku70/80 相关的临床试验

NCT06257758 / Recruiting临床1/2期

A Phase 1/2 Study of VIO-01 in Participants With Recurrent Solid Tumors

The goal of this phase 1/2 clinical trial is to investigate the safety of an investigational drug called VIO-01 when taken by people who have different types of solid tumor cancers. There are two parts to this trial, part 1 and part 2.
Part 1 of the trial aims to answer these questions:
The safety and tolerability of VIO-01 when it is given alone or in combination with other anti-cancer therapies.
The highest dose that people can take without having unacceptable side effects
How well your body tolerates the drug alone or in combination, how they are absorbed, and the effects they have on your disease.
Part 2 of the trial will further test VIO-01's effect in participants with advanced HRRm or HRD+ solid tumors and HRRm/HRD+ recurrent ovarian cancer.
Participants will follow a schedule of visits to the study site to have assessments done related to their health condition and to receive the trial treatment.

开始日期2024-01-10

申办/合作机构

Valerio Therapeutics SA

100 项与 Ku70/80 相关的临床结果

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100 项与 Ku70/80 相关的转化医学

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0 项与 Ku70/80 相关的专利（医药）

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项与 Ku70/80 相关的文献（医药）

2024-12-01·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

NHEJ is promoted by the phosphorylation and phosphatase activity of PTEN via regulation of DNA-PKcs

Article

作者: Islam, Md Maidul ; Gopi, Priyanka ; Pandya, Prateek ; Mukherjee, Ananda ; Chowdhury, Sougata Ghosh ; Karmakar, Parimal ; Misra, Sandip ; Ghosh, Ginia

DNA double-strand breaks (DSBs) are considered one of the most harmful forms of DNA damage. These DSBs are repaired through non-homologous end joining (NHEJ) and homologous recombination (HR) pathways and defects in these processes can lead to genomic instability and promote tumorigenesis. Phosphatase and Tensin homolog (PTEN) are crucial in HR repair. However, its involvement in the NHEJ repair pathway has remained elusive. In this study, we investigate the function of epigenetic regulation of PTEN in the NHEJ repair pathway. Our findings indicate that both the phosphorylation and phosphatase activity of PTEN are required for efficient NHEJ-mediated DSB repair. During the DNA damage response, we observed a reduced expression and chromatin attachment of the key NHEJ proteins, including Ku70/80, DNA-PKcs, XRCC4, and XLF, in PTEN-null cells. This reduction was attributed to the instability of these NHEJ proteins, as confirmed by our protein half-life assay. We have demonstrated that the DNA-PKcs inhibitor, NU7026, suppresses the DNA damage-induced phosphorylation of the C-terminal of PTEN. Thus, our study indicates that PTEN could be a target of DNA-PKcs. Protein-protein docking analysis also shows that PTEN interacts with the C-terminal region of DNA-PKcs. PTEN null cells exhibit compromised DNA-PKcs foci after DNA damage as it is in a hyper-phosphorylated state. Phospho-PTEN assists in recruiting DNA-PKcs on the DNA damage site by maintaining its hypo-phosphorylated state which also depends on its phosphatase activity. Therefore, after DNA damage, crosstalk between PTEN and DNA-PKcs modulates the NHEJ pathway. Thus, during DNA damage, PTEN gets phosphorylated directly or indirectly by DNA-PKcs and attaches to chromatin, resulting in the dephosphorylation of DNA-PKcs and subsequently recruitment of other NHEJ factors on chromatin occurs for efficient execution of the NHEJ pathway. Thus, our research provides a molecular understanding of the epigenetic regulation of PTEN and its significant role in controlling the NHEJ pathway.

2024-08-01·DNA Repair

KBM-mediated interactions with KU80 promote cellular resistance to DNA replication stress in CHO cells

Article

作者: Caldecott, Keith W ; Wells, Sophie E

The KU heterodimer (KU70/80) is rapidly recruited to DNA double-strand breaks (DSBs) to regulate their processing and repair. Previous work has revealed that the amino-terminal von Willebrand-like (vWA-like) domain in KU80 harbours a conserved hydrophobic pocket that interacts with a short peptide motif known as the Ku-binding motif (KBM). The KBM is present in a variety of DNA repair proteins such as APLF, CYREN, and Werner protein (WRN). Here, to investigate the importance of KBM-mediated protein-protein interactions for KU80 function, we employed KU80-deficient Chinese Hamster Ovary (Xrs-6) cells transfected with RFP-tagged wild-type human KU80 or KU80 harbouring a mutant vWA-like domain (KU80^L68R). Surprisingly, while mutant RFP-KU80^L68R largely or entirely restored NHEJ efficiency and radiation resistance in KU80-deficient Xrs-6 cells, it failed to restore cellular resistance to DNA replication stress induced by camptothecin (CPT) or hydroxyurea (HU). Moreover, KU80-deficient Xrs-6 cells expressing RFP-KU80^L68R accumulated pan-nuclear γH2AX in an S/G2-phase-dependent manner following treatment with CPT or HU, suggesting that the binding of KU80 to one or more KBM-containing proteins is required for the processing and/or repair of DNA ends that arise during DNA replication stress. Consistent with this idea, depletion of WRN helicase/exonuclease recapitulated the CPT-induced γH2AX phenotype, and did so epistatically with mutation of the KU80 vWA-like domain. These data identify a role for the KBM-binding by KU80 in the response and resistance of CHO cells to arrested and/or collapsed DNA replication forks, and implicate the KBM-mediated interaction of KU80 with WRN as a critical effector of this role.

2024-07-01·European Journal of Pharmacology

Discovery of UMI-77 as a novel Ku70/80 inhibitor sensitizing cancer cells to DNA damaging agents in vitro and in vivo

Article

作者: Lin, Zhonghui ; Chen, Changkun ; Chen, Xuening ; Liu, Jianyong ; Luo, Chengmiao

The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC₅₀ value of 2.3 μM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.

项与 Ku70/80 相关的新闻（医药）

2024-08-03

·生物探索

Sci Adv丨Frock团队发现复制前期可替代末端DNA修复和调控机制

引言 DNA双链损伤修复主要包括同源重组修复（HR），非同源末端修复（NHEJ）和可替代末端修复（A-EJ）。A-EJ主要在HR和NHEJ抑制的情况下起主要作用，这也是其名字的由来。例如在细胞有丝分裂期（M-phase），Brca2缺失的S/G2期，或Ku70/80或Lig IV缺失的G1/G0期 (复制前期)。A-EJ的主要组分包括Polθ, Polλ, Parp1/2, XRCC1和 Lig I/III，这些因子之间存在冗余性，在特定的条件下，使用哪些组合以及如何调控的并不清楚。斯坦福大学医学院Frock团队以小鼠前体v-Abl B淋巴细胞为研究对象，结合高通量DNA损伤修复捕捉技术Rejoin-HTGTS【1，2】，发现在Ku70缺失的复制前期，前体v-Abl B淋巴细胞仍然能通过Parp-XRCC1-Lig III A-EJ修复轴进行有限的V(D)J重组，且受到ATM和53BP1的调控。2024年7月31，相关工作发表在Science Advances, 题目为ATM and 53BP1 regulate alternative end joining-mediated V(D)J recombination。论文深入研究了A-EJ介导的V(D)J重组的特征。例如，在复制前期，存在微同源（microhomology）和片段删除（deletion）等A-EJ修复特征，但并没有出现明显的片段插入（insertion），因此也没有发现Polθ在该条件下起作用，尽管Polθ是细胞有丝分裂期的关键A-EJ因子【3，4】；而干扰Parp、XRCC1、Polα、ATM和53BP1对微同源的利用有不同程度的影响，并且Parp1和ATM有显著的叠加效应（图1）。图1.A-EJ相关因子在V(D)J重组中微同源利用率的作用（Credit: Science Advances） V(D)J重组的过程中，还可能伴随少量病理性的染色体易位（chromosome translocation），在小鼠细胞中染色体易位主要通过A-EJ介导，因此，在Ku70缺失的细胞中，进一步敲除53BP1导致染色体易位大量减少，这与V(D)J重组减少一致。而ATM的缺失使染色体易位明显增多，可能是因为ATM阻止原修复中心解离(图2）。有意思的是，Parp1敲除或者Parp1/2抑制的条件下却没有观察到明显的变化，这是由于基因组层面出现了更多的DNA损伤平衡了其A-EJ连接能力的下降。图2.ATM和53BP1对A-EJ介导的染色体易位的影响（Credit: Science Advances） A-EJ在许多癌细胞中高表达，不但使得通过细胞损伤杀死癌细胞变得困难，还增加了癌细胞进一步变异的能力。因此，A-EJ的主要成分被作为治疗癌症的靶点。目前，Parp作为靶点的许多治疗癌症的药物已经用于临床治疗，Polθ的一些癌症治疗药物也进入了临床二期。进一步深入研究A-EJ修复和调控机制也将为癌症治疗提供新的思路。参考文献 1. Liang, Z., Kumar, V., Le Bouteiller, M., Zurita, J., Kenrick, J., Lin, S.G., Lou, J., Hu, J., Ye, A.Y., Boboila, C., et al. (2021). Ku70 suppresses alternative end joining in G1-arrested progenitor B cells. Proc. Natl. Acad. Sci. U. S. A. 118. 10.1073/pnas.2103630118. https://www.pnas.org/doi/full/10.1073/pnas.2103630118 2. Wang, J., Sadeghi, C.A., and Frock, R.L. (2024). DNA-PKcs suppresses illegitimate chromosome rearrangements. Nucleic Acids Res. 52, 5048–5066. https://academic.oup.com/nar/article/52/9/5048/7614868 3. Gelot, C., Kovacs, M.T., Miron, S., Mylne, E., Haan, A., Boeffard-Dosierre, L., Ghouil, R., Popova, T., Dingli, F., Loew, D., et al. (2023). Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis. Nature 621, 415–422. https://www.nature.com/articles/s41586-023-06506-6 4. Brambati, A., Sacco, O., Porcella, S., Heyza, J., Kareh, M., Schmidt, J.C., and Sfeir, A. (2023). RHINO directs MMEJ to repair DNA breaks in mitosis. Science 381, 653–660. https://www.science.org/doi/10.1126/science.adh3694 https://www.science.org/doi/10.1126/sciadv.adn4682 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床结果临床2期