更新于：2024-04-01

TOP1

DNA拓扑异构酶I

更新于：2024-04-01

基本信息

别名

Ⅰ型DNA拓扑异构酶类、DNA topoisomerase 1、DNA topoisomerase I

+ [3]

简介

Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the BMAL1 promoter.

关联

201

项与 TOP1 相关的药物

Sacituzumab govitecan-hziy

戈沙妥组单抗

靶点

TOP1 x Trop-2

作用机制

TOP1抑制剂 [+1]

在研机构

Gilead Sciences, Inc. [+10]

原研机构

Immunomedics, Inc.

在研适应症

转移性三阴性乳腺癌 [+42]

非在研适应症

食管癌 [+9]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2020-04-22

Fam-trastuzumab deruxtecan-NXKI

德曲妥珠单抗

靶点

HER2 x TOP1

作用机制

HER2拮抗剂 [+1]

在研机构

第一三共（中国）投资有限公司 [+8]

原研机构

Daiichi Sankyo Co., Ltd.

在研适应症

非小细胞肺癌 [+42]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2019-12-20

Irinotecan Hydrochloride Lioposome

盐酸伊立替康脂质体

靶点

TOP1

作用机制

TOP1抑制剂

在研机构

石药集团欧意药业有限公司 [+8]

原研机构

Academic Medical Center University of Amsterdam [+1]

在研适应症

转移性胰腺腺癌 [+12]

非在研适应症

局部晚期胃食管交界处腺癌 [+2]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2015-10-22

2,986

项与 TOP1 相关的临床试验

NCT05733689 / Not yet recruiting临床1期IIT

Response Adapted Neoadjuvant Therapy in Gastroesophageal Cancers (RANT-GC Trial) - a Phase Ib Feasibility Trial

This is a phase 1b prospective, single arm, open-label trial determining the efficacy and feasibility of using a ctDNA assay (test) result to help guide neoadjuvant chemotherapy in subjects with Stage IB, II or Stage III adenocarcinoma of the stomach or gastroesophageal junction (GEA).

开始日期2025-02-01

申办/合作机构

University of California, Irvine

[+1]

NCT04199026 / Not yet recruiting早期临床1期IIT

Pilot Trial of an Implantable Microdevice for In Vivo Drug Sensitivity Testing in Patients With Sarcomas

This early phase I trial studies the side effects of implanting and removing a microdevice in patients with sarcomas that have spread to other places in the body (metastatic) or have come back (recurrent). Microdevices are rice-sized devices that are implanted into tumor tissue and are loaded with 10 different drugs that are delivered at very small doses, or "microdoses," which may only affect a very small, local area inside the tumor. The purpose of this study is to determine which drugs delivered in the microdevice affect tumor tissue in patients with sarcomas.

开始日期2025-01-31

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

NCT06315491 / Not yet recruiting临床2期

A Randomized Phase 2 Study of CBX 12 in Subjects With Platinum Resistant or Refractory Ovarian Cancer

The purpose of this study is to assess the safety, tolerability, and efficacy of CBX-12 in female subjects with platinum resistant or refractory ovarian cancer at 2 doses; 125 mg/m2 every 21 days or 100 mg/m2 every 21 days.

开始日期2024-07-01

申办/合作机构

Cybrexa, Inc.初创企业

100 项与 TOP1 相关的临床结果

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100 项与 TOP1 相关的转化医学

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0 项与 TOP1 相关的专利（医药）

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2,319

项与 TOP1 相关的文献（医药）

2024-03-15·iScience

TOP1 and R-loops facilitate transcriptional DSBs at hypertranscribed cancer driver genes.

Article

作者: Osama Hidmi ; Sara Oster ; Jonathan Monin ; Rami I Aqeilan

DNA double-stranded breaks (DSBs) pose a significant threat to genomic integrity, and their generation during essential cellular processes like transcription remains poorly understood. In this study, we employ several techniques to map DSBs, R-loops, and topoisomerase 1 cleavage complex (TOP1cc) to comprehensively investigate the interplay between transcription, DSBs, topoisomerase 1 (TOP1), and R-loops. Our findings reveal the presence of DSBs at highly expressed genes enriched with TOP1 and R-loops. Remarkably, transcription-associated DSBs at these loci are significantly reduced upon depletion of R-loops and TOP1, uncovering the pivotal roles of TOP1 and R-loops in transcriptional DSB formation. By elucidating the intricate interplay between TOP1cc trapping, R-loops, and DSBs, our study provides insights into the mechanisms underlying transcription-associated genomic instability. Moreover, we establish a link between transcriptional DSBs and early molecular changes driving cancer development, highlighting the distinct etiology and molecular characteristics of driver mutations compared to passenger mutations.

2024-02-16·Annals of oncology : official journal of the European Society for Medical Oncology

Translational Insights and Overall Survival in the U31402-A-U102 Study of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC.

Article

作者: H A Yu ; C Baik ; D-W Kim ; M L Johnson ; H Hayashi ; M Nishio ; J C-H Yang ; W-C Su ; K A Gold ; M Koczywas ; E F Smit ; C E Steuer ; E Felip ; H Murakami ; S-W Kim ; X Su ; S Sato ; P-D Fan ; M Fujimura ; Y Tanaka ; P Patel ; D Sternberg ; D Sellami ; P A Jänne

BACKGROUND:

HER3 is broadly expressed in NSCLC and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase 1 study of HER3-DXd in patients with advanced NSCLC. Patients with EGFR-mutated NSCLC that progressed after EGFR TKI and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd.

PATIENTS AND METHODS:

Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC.

RESULTS:

In the safety population (N=102), median treatment duration was 5.5 (range, 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (per RECIST v1.1) was 41.0% (95% CI, 30.0%-52.7%), median progression-free survival was 6.4 (95% CI, 4.4-10.8) months, and median OS was 16.2 (95% CI, 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified.

CONCLUSION:

In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

2024-02-10·Nucleic acids research

G-quadruplexes on chromosomal DNA negatively regulates topoisomerase 1 activity.

Article

作者: Hui-Ting Liang ; Jiang-Yu Yan ; Hao-Jun Yao ; Xue-Nan Zhang ; Zhi-Ming Xing ; Lin Liu ; Yao-Qing Chen ; Guo-Rui Li ; Jing Huang ; Yi-de He ; Ke-Wei Zheng

Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.

130

项与 TOP1 相关的新闻（医药）

2024-03-25

·BioSpace

ProLynx announces initiation of the Phase II Topology clinical trial of its DNA-damaging agent PLX038 in triple-negative breast cancer at the Institut Curie

SAN FRANCISCO, March 25, 2024 (GLOBE NEWSWIRE) -- ProLynx Inc. announced that the first patient was included in TOPOLOGY by investigator Dr. Delphine Loirat, with a Phase II clinical trial investigating PLX038 (PEG~SN-38) for locally-advanced or metastatic triple-negative breast cancer (TNBC). Patients will have been previously treated with at least two therapies, including the antibody-drug conjugate (ADC) sacituzumab govitecan (SG; Trodelvy). The TOPOLOGY trial is run by Institut Curie (Paris and Saint Cloud, France), with principal investigator Prof. Francois-Clement Bidard . PLX038 is a long-acting prodrug of the topoisomerase 1 (Top1) inhibitor, SN-38, which is also the active component of anti-cancer agents irinotecan and the ADC SC. Top1 inhibitors cause DNA breaks and kill tumors that are unable to repair the damage. Previously, Curie researchers showed that about one-third of TNBC patients have defects in DNA damage repair, and should respond to an effective SN-38-based therapy (Coussy et al., 2020). In PLX038, SN-38 is covalently bound to a circulating nanoparticle and is slowly released to provide free SN-38 with a long half-life, low Cmax, and high exposure – important facets for optimal safety and efficacy. Importantly, in preclinical studies PLX038 was shown to accumulate and be retained in solid tumors, where it slowly releases its SN-38. SG is an anti-TROP2 ADC with an SN-38 payload that was recently approved for use in advanced TNBC. However, the rapid spontaneous linker hydrolysis in SG releases a large amount of SN-38 cargo systemically, which may in part contribute to its efficacy and also in part be responsible for systemic side effects. Unfortunately, the median progression-free survival after SG therapy is only ~6 months due to resistance, and there are limited rescue therapies available. ProLynx co-founder and President Daniel V. Santi commented, “Although the active SN-38 payload of PLX038 and SG is the same, the anti-tumor mechanisms of the prodrugs are quite different; and, some mechanisms of resistance may also quite be different (Santi et al., Biodrugs,2024). Taken together, it is reasonable to believe that PLX038 may be effective in SG-resistant tumors.” Curie investigator Francois-Clement Bidard added, “As with our earlier preclinical study of the correlation of efficacy of irinotecan with BRCAness and SFLN11 biomarkers, TOPOLOGY will assess association of PLX038 efficacy with homologous recombination defects, and biomarkers such as SFLN11 expression and RB1 loss. If confirmed in TOPOLOGY, these biomarkers will allow pre-selection of patients most likely to respond to the drug.” ProLynx is a San Francisco biotechnology company developing proprietary systems to improve the pharmacokinetics and efficacy of important therapies ( ). Institut Curie, France’s leading cancer center, combines a renowned research center and hospital which treats all types of cancer. Institut Curie has 3 sites (Paris, Saint-Cloud and Orsay) with over 3,700 health professionals working on treatment, research and teaching ( ) Information on this clinical trial is available at clinicaltrials.gov, NCT06162351. Contact BD@ProLyninc.com

临床2期抗体药物偶联物

2024-03-19

·医药地理

第一三共/阿斯利康TROP2 ADC在中国申报上市

3月16日，第一三共/阿斯利康联合开发和推广的TROP2 ADC德达博妥单抗（datopotamab deruxtecan，Dato-DXd）的新药上市许可申请正式获药监局受理，用于治疗既往在不可切除或转移性疾病阶段接受过系统治疗的HR阳性、HER2阴性（IHC 0、IHC 1+或IHC 2+/ISH-）的不可切除或转移性乳腺癌成人患者。 Datopotamab deruxtecan（Dato-DXd）是一款靶向TROP2的ADC，采用第一三共专有的DXd ADC技术设计，由人源化抗TROP2 IgG1单克隆抗体（与札幌医科大学合作开发）通过可裂解的四肽连接子，与拓扑异构酶I抑制剂有效载荷（喜树碱类衍生物）连接组成。内容来源于网络，如有侵权，请联系删除。

抗体药物偶联物

2024-03-13

·药研网

B7-H4: 泛癌靶点新星持续发力

B7-H4是B7家族重要成员之一，也称为B7S1或VTCN1。它是一种I型跨膜蛋白，含有282个氨基酸，由一个信号肽区、一个由IgV和IgC结构域组成胞外区、一个跨膜区和一个胞内区组成。人类B7-H4 mRNA在正常组织中广泛表达，但B7-H4蛋白的表达受到严格控制。到目前为止，B7-H4的受体仍然未知的。多项研究证实，B7-H4在多种肿瘤细胞（尤其是卵巢癌、胆管上皮癌、乳腺癌、子宫内膜癌）、抗原呈递细胞和肿瘤相关巨噬细胞中过表达，发挥着负协同共刺激分子的作用，对癌症的发生和免疫有着重要作用。B7-H4可通过参与多种细胞信号转导通路，增强肿瘤细胞的增殖、侵袭、转移和抗凋亡能力，从而促进肿瘤进展。此外，研究表明，在炎症、自身免疫性疾病、病毒感染或妊娠的个体中可检测到B7- H4的异常表达。免疫调节抑制T细胞增殖、抑制T细胞的活化、抑制体液免疫反应、调节先天免疫感应、参与炎症反应促进肿瘤的发生和发展促进肿瘤细胞的增殖和分化、促进肿瘤细胞的侵袭和转移、抑制肿瘤凋亡、促进肿瘤血管生成抑制了T细胞对β细胞的反应，从而防止了β细胞被破坏其他生物学功能预防妊娠期免疫性疾病；可溶性血清 B7-H4 水平与肿瘤分期、不良预后和病理类型相关等目前，全球针对B7-H4靶点开发的药物有很多，包括单克隆抗体、双抗、ADC等，但还没有被FDA批准的靶向B7-H4的治疗或药物上市。目前最快的进度处于临床2期。 HS-20089 是一种针对 B7-H4 的新型 DAR-6 抗体-药物偶联物(ADC)，其有效载荷为拓扑异构酶抑制剂（TOPOi） 2023年10月20日，葛兰素史克（GSK）以8500万美元首付款和14.85亿美元里程碑付款引进翰森制药开发的B7-H4 ADC药物HS-20089大中华区以外权益，交易总额达15.35亿美元。在临床前研究中发现，HS-20089在体外和体内可抑制表达B7-H4的肿瘤细胞生长。在初步临床实验数据显示，该ADC药物在晚期实体瘤患者中表现出良好的耐受性和抗肿瘤活性。在研适应症有输卵管癌、原发性腹膜癌、子宫内膜癌、卵巢癌、晚期恶性实体瘤、女性生殖器官肿瘤和实体瘤，作为抗体药物ADC赛道的强势一员，想必HS-20089在不久的将来，必能令人欢欣鼓舞。 AZD-8205是阿斯利康旗下的一种携带新型拓扑异构酶I抑制剂(TOP1i)有效载荷的B7-H4靶向ADC 该款药物在研适应症主要也是胆道肿瘤、乳腺癌、胆管上皮癌等实体瘤，临床试验在中国和美国同步开展。单独使用或与PARP1选择性抑制剂AZD5305联合使用。在临床前研究中，AZD8205在各种患者来源的异种移植模型中显示出有希望的抗肿瘤活性和可接受的毒性特征。AZD-8205和HS-20089必将是强劲的对手，让我们拭目以待谁将更胜一筹。 NC762是NextCure和Five Prime Therapeutics联合开发的B7-H4单抗 NC762为DLE突变（S239D/A330L/I332E）的ADCC增强型B7-H4抗体，在2021年7月启动了在肺癌、HER2+乳腺癌、卵巢癌或其他潜在肿瘤类型患者中的1/2期临床试验。在体内试验表现出剂量依赖的抗肿瘤活性。 2023年7月10日，百济神州与映恩生物达成合作，共同推进BG-C9074的研发和商业化。2024年1月31日，百济神州在Clinicaltrials.gov网站上注册了BG-C9074的美国一期临床试验。根据注册信息，BG-C9074为一款B7H4靶向ADC新药。此次一期临床计划入组150例晚期实体瘤患者。根据百济神州公开信息，其B7H4 ADC采用经过临床验证的linker、强旁观者杀伤效应、DAR6设计。“ 目前不管是国内还是国外的药企都在积极布局B7-H4，虽然目前市场上还没有 B7-H4 药物，但其在各种肿瘤组织（包括卵巢癌、乳腺癌、膀胱癌和胰腺癌）中的高表达表明 B7-H4 作为癌症药物开发靶点的巨大潜力。我们期待在药企的不懈努力下，B7-H4能够迎来首款药物，造福广大患者。” 参考文献： 1.https://doi.org/10.1016/j.tips.2019.09.008 2.https://doi.org/10.1016/j.cellimm.2019.104008 内容来源于网络，如有侵权，请联系删除。