A Single-Dose, Bioequivalence and Food Effect Bioavailability Study in Healthy Volunteers Comparing the Commercial Lumacaftor 200 mg / Ivacaftor 125 mg Combination Film-Coated Tablet (Orkambi®) to the Lumacaftor 200 mg Film-Coated Tablet Formulation, and the Lumacaftor 200 mg Film-Coated Tablet Formulation in the Fasted to Fed State.

The objective of this study is to assess bioequivalence of lumacaftor from Lumacaftor 200 mg Film-Coated Tablet Formulation (Qanatpharma) versus the reference commercial product, Lumacaftor 200 mg /Ivacaftor 125 mg Combination Film-Coated Tablet (Orkambi®) in the fed state, and food-effect bioavailability of Lumacaftor 200 mg Film-Coated Tablet Formulation (Qanatpharma) in the fasted and fed state in healthy, non-smoking, male and non-pregnant female volunteers, 18 to 55 years of age, inclusive.

开始日期2023-11-17

申办/合作机构-

NCT04581408

/ Completed临床2期IIT

Mutation-specific Therapy for the Long QT Syndrome

Novel therapy for the Long QT Syndrome based on the mechanism of action of the disease-causing mutations
Long QT syndrome type 2 (LQT2) accounts for
35% of all LQTS cases and is difficult to manage, as beta-blockers frequently fail to provide full protection. Most LQT2 patients (pts) have a Class 2 mutation, which implies defective "trafficking".
Lumacaftor (LUM) is a drug developed and currently indicated for the treatment of cystic fibrosis (CF) in patients homozygous for the F508del mutation in the CFTR gene. LUM corrects protein folding and trafficking defects of mutant and misfolded CFTR channels, restoring their cell surface expression. The investigators recently demonstrated that LUM can rescue in vitro the LQTS phenotype observed in human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) from pts with LQT2 Class 2 mutations (PMID: 29020304) and in these same two patients Orkambi administrated for 7 days at the same dosage approved for cystic fibrosis showed to reduce their QTc (PMID: 30753398).
With the present phase II clinical trial (MAST2) the investigators will enroll 20 LQT2 patients (see inclusion and exclusion criteria) and they will test in vivo the efficacy of Orkambi in shortening their QTc. Patients will be admitted to hospital for a maximum of 7 days (minimum in-hospital stay based on evidence of QTc shortening). Orkambi will be administered at the dose approved for cystic fibrosis and during the entire period continuous ECG monitoring through both telemetry and 12-lead 24-hr Holter monitoring will be performed and QTc length and morphology will be analyzed.

开始日期2021-06-15

申办/合作机构

Istituto Auxologico Italiano

NCT04415268

/ WithdrawnN/AIIT

Combined Effect of CFTR Protein Modulator Drugs and Exercise on Pulmonary Function, Fitness, Sweat Test and Quality of Life in Children With Cystic Fibrosis

This study aims to assess the effects of programmed exercise combined with CFTR protein modulator drugs in the cardiorespiratory fitness, strength, functional capacity and agility in a group of young patients with Cystic Fibrosis.

开始日期2020-06-09

申办/合作机构

Universidad Europea de Madrid SAU

100 项与芦马卡托相关的临床结果

登录后查看更多信息

100 项与芦马卡托相关的转化医学

登录后查看更多信息

100 项与芦马卡托相关的专利（医药）

登录后查看更多信息

792

项与芦马卡托相关的文献（医药）

2025-05-01·JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES

Quantification of Ivacaftor, Tezacaftor, Elexacaftor, and Lumacaftor and their active metabolites in plasma using UHPLC-MS/MS: Doors open to the application of therapeutic drug monitoring in cystic fibrosis treatment

Article

作者: Akkerman, Onno W ; Wessels, A Mireille A ; Koppelman, Gerard H ; Mian, Paola ; Elzinga, Femke A ; Touw, Daan J

An ultra-high performance liquid chromatography-tandem mass spectrometry method was developed to quantify the cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor, tezacaftor, elexacaftor, and lumacaftor and their active metabolites hydroxymethyl ivacaftor, tezacaftor M1, and N-desmethylelexacaftor in human EDTA plasma. The analytical method utilized protein precipitation with stable isotope dilution for sample preparation, facilitating a simple and rapid assay, with a total runtime of only 2.1 min. Separation of the seven components and stable isotope-labeled internal standards was achieved on a C₁₈ column, followed by detection using a tandem quadrupole mass spectrometer. Validation of the method was conducted in accordance with the "Bioanalytical Method Validation Guidance for Industry," of the Food and Drug Administration and with European Medicines Agency's "Guidance on bioanalytical method validation". The assay covers concentrations ranging from 0.010 to 10 mg/L for ivacaftor, hydroxymethyl ivacaftor and N-desmethylelexacaftor, from 0.025 to 25 mg/L for elexacaftor and tezacaftor, from 0.050 to 50 mg/L for tezacaftor M1 and from 0.100 to 100 mg/L for lumacaftor, using a sample volume of 10 μL. Matrix comparison confirmed the applicability of the assay to human serum and heparin plasma. Stability experiments indicated stability of the CFTR modulators in EDTA plasma over ten days under different conditions. At room temperature, all seven components remained stable for eight days and for ten days in the refrigerator in EDTA plasma and in EDTA whole blood. All seven components were stable in EDTA plasma for ten days in the autosampler after sample preparation and through four freeze-thaw cycles. The developed assay was applied in routine TDM analysis to investigate exposure to elexacaftor, tezacaftor, ivacaftor and their metabolites in people with CF undergoing treatment with Kaftrio®.

2025-05-01·THERAPIE

Article

作者: Blaisonneau, Elora ; Belleguic, Chantal ; Polard, Elisabeth ; Mercerolle, Marion ; Bacle, Astrid ; Osmont, Marie-Noëlle ; Le Daré, Brendan ; Triquet, Louise

INTRODUCTION:

Cystic fibrosis transmembrane regulator (CFTR) channel modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) represent a major advance in the management of cystic fibrosis. However, few data are available on the real-life safety profile of these medications, in particular on adverse events that may lead to their discontinuation. The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France).

MATERIALS AND METHODS:

A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France.

RESULTS:

Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case.

CONCLUSION:

This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of "caftors", their possible risk factors, and the impact of adjusting dosing modalities.

2025-05-01·Anales de pediatria

Advances in the treatment of cystic fibrosis: CFTR modulators

Review

作者: Martín de Vicente, Carlos ; González Jiménez, David ; Vicente-Santamaria, Saioa ; Costa I Colomer, Jordi ; Luna Paredes, Carmen ; Pastor-Vivero, Maria Dolores ; Garcia Romero, Ruth

Cystic fibrosis is a severe genetic disease caused by variants in the CFTR gene. Although it is a multisystem disease, respiratory involvement is the main cause of morbidity and mortality. Cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapies have advanced the treatment of this disease by improving function of this protein. Ivacaftor, the first CFTRm, has been found to significantly improve lung function and quality of life in patients with certain gating variants. However, only a small percentage of patients in Spain are eligible for this treatment. Combinations of correctors and potentiators, such as lumacaftor-ivacaftor or tezacaftor-ivacaftor, have been developed for treatment of patients with the most frequent variant (F508del), although with limited benefits. Triple therapy with elexacaftor-tezacaftor-ivacaftor has been found to significantly improve respiratory, gastrointestinal and nutritional outcomes as well as quality of life, thus changing the management of CF in eligible patients. The impact of triple therapy is also reflected in an increase in life expectancy and a decrease in mortality and lung transplantation. As regards hepatic and pancreatic involvement, while CFTR modulators have exhibited promising effects, further research is required. The use of CFTR modulators has also shifted nutritional status trends in patients with CF, reducing the risk of undernutrition but increasing the risk of obesity. The use of these drugs for treatment of less frequent variants and for potential antenatal treatment is currently being investigated. Despite these advances, there is still a subset of patients who are ineligible for treatment with modulators or highly effective therapy.

项与芦马卡托相关的新闻（医药）

2024-12-19

·PRNewswire

A Success Story: Digital Opinion Leader Analysis for Cystic Fibrosis Treatments | DelveInsight

A case study on how a pharmaceutical company specializing in cystic fibrosis treatments turned to DelveInsight for comprehensive analysis and insights into the digital cystic fibrosis landscape in the UK. DelveInsight identified key Digital Opinion Leaders (DOLs) and synthesized their opinions, enabling the client to strategically leverage these insights for drug development, marketing, and patient advocacy, ensuring a competitive edge in the cystic fibrosis market. LAS VEGAS, Dec. 19, 2024 /PRNewswire/ -- DelveInsight, a leader in healthcare competitive intelligence and consulting company, published a success study on Digital Opinion Leader (DOL) Analysis in the Cystic Fibrosis Market . A pharmaceutical company specializing in cystic fibrosis treatments approached DelveInsight to conduct an in-depth analysis of DOLs in the UK. The client sought to identify key digital influencers and understand their perspectives on cystic fibrosis treatments, leveraging these insights to inform drug development, marketing strategies, and patient advocacy efforts. Cystic fibrosis is a life-limiting autosomal recessive genetic disorder that primarily affects the lungs and digestive system, caused by mutations in the CFTR gene. According to DelveInsight's latest Cystic Fibrosis Market and Epidem Forecast Report, the estimated total diagnosed prevalent cases of cystic fibrosis in the 7MM in 2023 were ~68K cases. The UK had the highest number of diagnosed cystic fibrosis cases, with nearly 11K, followed by France with 7.5K and Germany with 7K. In the EU4 and the UK, the cystic fibrosis market size was nearly USD 7 billion, accounting for almost 39.4% of the total 7MM market size in 2023. This is expected to increase significantly by 2034. Download the Sample Report to Explore Future Trends in the Cystic Fibrosis Market In the field of cystic fibrosis, DOLs play a significant role in shaping perceptions and influencing the direction of treatment, policy, and patient care. These are influential healthcare professionals or researchers who have an active online presence and contribute to discussions, research, and advocacy. For pharmaceutical companies developing cystic fibrosis treatments, understanding the DOL landscape is crucial for gaining insights into market dynamics and stakeholder perceptions and identifying strategic opportunities for drug development, marketing, and patient advocacy. Several medications have been approved to manage cystic fibrosis, with therapies targeting the CFTR protein to correct its defects. One of the most groundbreaking treatments is TRIKAFTA, a combination of elexacaftor, tezacaftor, and ivacaftor, which has revolutionized cystic fibrosis treatment by improving lung function in patients with specific genetic mutations. Other notable drugs include SYMDEKO (tezacaftor/ivacaftor) and ORKAMBI (lumacaftor/ivacaftor), which also target the CFTR protein. These therapies aim to address the root cause of the disease, improving symptoms and quality of life for patients. However, despite these advancements, the current treatment landscape still faces challenges, such as variability in treatment efficacy and accessibility to newer therapies for certain patient populations. The pipeline for cystic fibrosis treatments continues to evolve, with several promising drugs in the cystic fibrosis pipeline. Ensifentrine (Verona Pharmaceuticals) is a dual inhibitor of the enzymes responsible for inflammation and mucus production in the lungs, showing potential as an add-on therapy for patients with CF. VX-121/TEZ/VX-561 (Vertex Pharmaceuticals) is another exciting treatment, combining triple therapy to enhance CFTR function and improve lung function. LAU-7b (Laurent Pharmaceuticals Inc.) aims to restore CFTR function and reduce inflammation. Lonodelestat (Pari Pharma GmbH) is being investigated for its ability to reduce neutrophil elastase and inflammation in the lungs of CF patients. These drugs, if successful, could significantly improve treatment options and outcomes for CF patients. Several companies are at the forefront of developing treatments for cystic fibrosis. Eloxx Pharmaceuticals, Inc. focuses on treatments that aim to restore protein function in CF patients with specific genetic mutations. Vertex Pharmaceuticals is a leader in the CF market, with therapies like TRIKAFTA and ongoing pipeline developments. Santhera Pharmaceuticals is exploring potential treatments to address pulmonary issues in CF patients. DelveInsight helped the client by curating insights from the digital cystic fibrosis landscape and analyzing the opinions of key digital influencers. By identifying and analyzing these DOLs, DelveInsight provided actionable insights and strategic recommendations for the client. The company gained a deeper understanding of the market dynamics, stakeholder perceptions, and the evolving digital landscape surrounding cystic fibrosis. These insights were invaluable for informing drug development strategies, understanding the gaps, patient burden,, and patient advocacy initiatives. Armed with comprehensive information on DOLs and their impact, the client was better equipped to make informed decisions, enhance patient engagement, and improve the overall market approach for cystic fibrosis treatments. Our client approached us with multiple objectives: Understand the DOL Landscape in the UK for cystic fibrosis. Identify Key Digital Opinion Leaders influencing discussions about cystic fibrosis. Analyze the Opinions of DOLs on treatment options and emerging therapies. Leverage Insights to refine drug development, marketing strategies, and patient advocacy efforts. Outcome of DelveInsight's Digital Opinion Leader Analysis: We identified and profiled key digital opinion leaders (DOLs) in the UK cystic fibrosis community, focusing on those with strong online presence, high engagement, and CF expertise. Through content analysis, we gained insights into opinions, trends, and key areas like treatment, patient care, advocacy, and research within the CF community. We mapped the CF digital ecosystem, highlighting connections and interactions between DOLs and stakeholders revealing network dynamics and engagement patterns. We assessed the impact of DOLs using metrics like follower count, engagement rate, and content virality, helping clients prioritize engagement strategies and collaborations. DelveInsight specializes in comprehensive Key Opinion Leader (KOL) and Digital Opinion Leader (DOL) opinion analysis, offering deep insights into industry trends, expert perspectives, and influencer dynamics. Our expertise enables clients to identify and understand the nerve of the trends by providing analysis through the most impactful thought leaders and digital influencers. By leveraging our tailored strategies and data-driven approaches, we help businesses strengthen their approach, refine decision-making, and amplify their market impact. Connect with us today to explore how we can support your specific needs and discuss opportunities for strategic engagement. Request a Proposal Now ! Why Choose DelveInsight? DelveInsight offers comprehensive expertise in the respiratory disease domain, providing in-depth market research, consulting services, and pipeline analysis tailored to the evolving needs of the industry. With a sharp focus on respiratory conditions, DelveInsight delivers robust reports covering emerging therapies, market trends, competitive landscapes, and unmet needs. DelveInsight's respiratory-specific solutions empower stakeholders to make data-driven decisions, optimize their R&D efforts, and seize growth opportunities in the dynamic and rapidly advancing respiratory disease market. Market Assessment Services in the Genetic Disorders Segment, DelveInsight, provide a 360-degree view of the market landscape. Our expertise includes epidemiology-based market forecasts up to 2034, offering precise insights into current and future market share uptake of emerging therapies. These forecasts, combined with detailed analyses of emerging trends, competitive dynamics of the pipeline therapies, and unmet needs, enable stakeholders to strategize effectively and identify growth opportunities. Whether it's the pipeline analysis, pricing strategies, or competitive benchmarking, DelveInsight delivers actionable intelligence tailored to your goals. Contact us Today to discuss how our services can drive success in your endeavors within the genetic disorder market. Competitive Intelligence Services Tailored to Genetic Disorder Domain: DelveInsight's competitive intelligence services provide real-time, accurate insights across the different therapeutic domains and genetic disorders being one of our fortes, providing detailed insights into advancements across rare and inherited conditions such as cystic fibrosis, Duchenne muscular dystrophy, and sickle cell anemia etc to name a few. Our services analyze competitors' pipelines, clinical trial progress, gene and cell therapy innovations, and market entry strategies, as well as regulatory updates and patent landscapes specific to genetic disorders. This intelligence enables stakeholders to identify emerging threats, uncover growth opportunities, and develop targeted strategies to remain competitive in this evolving therapeutic area. Connect with us today to explore how we can help you succeed in the genetic disorders market. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform , PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

上市批准

2024-08-04

·奇点网

结直肠癌借道胆固醇代谢途径实现免疫逃逸。

*仅供医学专业人士阅读参考风谲云诡的肿瘤微环境，是肿瘤细胞生长和发展的场所，也是肿瘤细胞与免疫细胞明争暗斗的战场。在这里，肿瘤细胞能够通过重编程自身的代谢途径以抑制抗肿瘤免疫反应。例如，由肿瘤细胞产生的过量延胡索酸、氨和亚油酸会在肿瘤微环境中积累，抑制CD8+T细胞的浸润和激活，从而减少它们的抗肿瘤效应。近日，武汉大学李友军团队提出了结直肠癌巧用代谢进行免疫逃逸的新机制，论文于近日发表在《自然·通讯》上。他们揭示，结直肠癌细胞表达的双特异性磷酸酶18（DUSP18）通过调控胆固醇代谢途径，导致肿瘤细胞积累羊毛甾醇并将其释放到肿瘤微环境里，从而抑制CD8阳性T细胞的活性和浸润，介导肿瘤免疫逃逸。在结直肠癌患者中，DUSP18的高表达与免疫低反应的“免疫沙漠”肿瘤微环境有关。通过抑制DUSP18，可以显著削弱结直肠癌细胞对T细胞的免疫抑制作用，增强PD-1抑制剂的疗效。论文首页截图首先，李友军团队一方面利用CRISPR技术等方法和免疫功能缺陷或正常的小鼠，筛选找出了一些具有促进肿瘤免疫逃避潜力的基因，如Ptgs1和Dusp18等。另一方面，根据癌症基因组图谱（TCGA）-结肠腺癌（COAD）数据集，他们分析表明细胞毒性T淋巴细胞水平高与患者生存率高相关，并且计算得出735个基因与细胞毒性T淋巴细胞水平呈负相关。分析这两组基因之间的交集后，Dusp18最引人注意。结直肠癌样本中DUSP18 mRNA表达高于正常组织，并与几种关键免疫相关基因表达呈负相关，与CD8+T细胞浸润呈正相关。生存率分析表明，细胞毒性T细胞水平高且Dusp18表达水平低的患者生存更好，而Dusp18表达高的患者生存较差。找到和肿瘤免疫抑制相关的Dusp18结直肠癌小鼠实验结果显示，使用RNA干扰技术抑制Dusp18表达，或者特异性敲除肠上皮的Dusp18基因，在免疫功能正常的小鼠中能够显著抑制肿瘤生长并延长生存时间，而且这个效果依赖于其编码蛋白DUSP18的磷酸酶活性。此外，流式细胞术、免疫组化染色等分析结果显示，Dusp18抑制显著增加了CD8+T细胞的浸润和活性，同时减少了T细胞衰竭标志物（PD-1、TIM-3、CTLA-4）的表达，而对CD4+T细胞和自然杀伤细胞影响不大，也没有对肿瘤细胞的增殖造成影响。以上结果提示，Dusp18的表达及其编码蛋白DUSP18的磷酸酶活性，对CD8+T细胞的浸润和细胞毒性功能至关重要。目标已经锁定，接下来便要揪出其背后的信号通路。研究结果表明，在肿瘤细胞里，DUSP18通过去磷酸化修饰转录因子USF1，使其不易被泛素化降解。这种稳定作用促进USF1上调SREBF2基因表达，导致肿瘤细胞里积累胆固醇生物合成中间体羊毛甾醇，并促使将羊毛甾醇释放到肿瘤微环境中。羊毛甾醇被肿瘤微环境中的CD8+T细胞摄取后，通过抑制胞内KRAS/ERK信号通路限制CD8+T细胞的细胞毒性功能和激活。体外实验结果显示，使用羊毛甾醇处理，能够以剂量依赖性方式降低CD8+T细胞活化标志物CD69的表达，并抑制CD8+T细胞增殖、促进其凋亡，增加免疫检查点分子的表达。机制针对DUSP18，研究团队从ZINC15化合物库中大约两千种FDA批准的药物中，筛选出Lumacaftor作为具有最高结合能的DUSP18潜在抑制剂，能够与DUSP18的几个关键残基相互作用。Lumacaftor此前在囊性纤维化的治疗中被用来促进某些突变CFTR蛋白到外膜的转运。结直肠癌小鼠实验结果显示，相比于单独治疗或对照组，Lumacaftor与PD-1抑制剂联合治疗能够显著抑制肿瘤生长并延长小鼠的生存时间。此外，联合治疗显著增加了肿瘤中CD8+T细胞的比例，并提高其颗粒酶和IFN-γ的表达，显示出Lumacaftor在抑制DUSP18活性、减少肿瘤免疫逃逸和增强免疫疗法反应中的潜力。Lumacaftor增加结直肠癌小鼠对免疫治疗敏感性研究团队还收集了来自临床的80多个结直肠癌患者的样本，并结合TCGA-COAD数据集，分析表明DUSP18高表达的结直肠癌倾向于“免疫沙漠”，具有较少的免疫细胞浸润和效应活性，DUSP18高表达与结直肠癌患者的TMN分期呈正相关，并预示着患者更差的生存。DUSP18在结直肠癌患者中过度表达并预示免疫沙漠的存在这项研究揭示了DUSP18/USF1/SREBF2-羊毛甾醇信号通路在肿瘤免疫抑制重编程中发挥的关键作用，支持联合免疫检查点阻断和代谢阻断是结直肠癌的潜在有效治疗策略，可以同时针对免疫系统和肿瘤代谢。另外，DUSPs被认为是包括癌症在内多种疾病中信号通路的关键调节器，分为多种亚型。尽管PTEN和MKP亚型被广泛研究，其他亚型尤其是非典型DUSPs的研究相对较少。DUSP18正是属于非典型DUSPs，此次被证明在结直肠癌中表达上调，与患者临床进展显著相关。参考文献：[1]Zhou, X., Wang, G., Tian, C. et al. Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer. Nat Commun 15, 5851 (2024). https://doi.org/10.1038/s41467-024-50138-x本文作者丨张艾迪

免疫疗法信使RNA

2024-07-12

·精准药物

DUBTAC揭示新型靶向治疗的未来

来源：药渡撰文：balabala 编辑：哦呼靶向嵌合体蛋白水解（PROTAC）技术代表了药物发现领域的突破性发展，利用泛素蛋白酶体系统特异性降解与疾病相关的蛋白质，多项目已进入临床开发。但针对CF和某些癌症，需开发靶向蛋白稳定剂TPS以对抗异常蛋白降解。拓展阅读：瞄准靶蛋白降解：中国在PROTAC药物战略布局中的新动向 PROTAC设计中Linker特性的探索与创新靶向“不可成药”靶点，浅析PROTAC、分子胶靶向蛋白降解与靶向蛋白稳定技术推动PROTAC药物开发新纪元：扩展PROTAC的E3连接酶靶向蛋白质稳定技术（targeted protein stabilization，TPS）是近年来生物医学领域一种新兴的技术，旨在通过特定的方法来稳定细胞内的蛋白质，从而影响其功能和行为。这种技术潜在应用广泛，从基础研究到新药开发都有重要价值。去泛素化酶靶向嵌合体（deubiquitinase-targeting chimeras，DUBTACs）是近年来逐渐发展的一种靶向蛋白质稳定技术，DUBTACs一般由靶蛋白配体、去泛素化酶配体和Linker三部分组成，这样的结构设计使得DUBTAC分子可以同时结合靶蛋白和去泛素化酶，诱导靶蛋白和去泛素化酶靠近，去除靶蛋白上的泛素链，从而达到稳定以泛素化依赖方式降解的特定蛋白质的水平（图1）。图1. DUBTAC平台在这里，我们总结了近年来DUBTAC技术的研发进展，详细探讨了其在生物医药领域的应用前景和潜在挑战。 01 基于OUTB1的DUBTACs 在2022年初，加州大学伯克利分校的Daniel K. Nomura教授团队运用基于活性的蛋白质图谱分析（activity-based protein profiling, ABPP）对65种去泛素化酶的反应性半胱氨酸进行全局性分析。研究结果发现，泛素化酶OTUB1的C23位点不参与酶活性的调控且具有较高的亲核性，是一个理想的配体结合位点。由于细胞中主要介导蛋白质降解的最丰富的泛素链是K48链，而OTUB1则是靶向移除K48链的去泛素化酶。理论上，利用OTUB1去针对性地去除特定蛋白上的泛素链，防止以泛素化依赖方式被降解的特定蛋白质被蛋白酶体降解，是非常有效的。图2. EN523结构（1）ΔF508-CFTR-DUBTACs Daniel K. Nomura教授团队基于上述发现筛选出了一个与OUTB1高亲和力结合的共价配体EN523（图2）。其中，EN523与OTUB1结合是通过EN523的丙烯酰胺部分与OTUB1变构半胱氨酸残基Cys23共价作用来实现的。他们通过体外实验证明EN523对OTUB1的酶活性没有显著影响。随后，研究人员将筛选到的EN523与ΔF508-CFTR调节剂Lumacaftor连接起来所获得的异源双功能小分子NJH-2-057用于靶向CFTR突变体ΔF508-CFTR的稳定从而改善囊性纤维化。实验结果表明，NJH-2-057可以有效稳定ΔF508-CFTR，而单独使用Lumacaftor的结果则与对照组差异不明显（图3）。这一结果为DUBTAC技术的发展提供了概念验证。图3. NJH-2-057稳定CFTR （2）WEE1-DUBTACs Daniel K. Nomura教授团队随后将DUBTAC技术应用于提高抑癌基因WEE1的稳定性，WEE1是一种非恶性真核体细胞中的肿瘤抑制激酶，可磷酸化细胞周期蛋白依赖性激酶（CDK1）-细胞周期蛋白B1复合物，以抑制有丝分裂S期和G2期的细胞周期进展，并且必须下调其活性才能发生有丝分裂进展。WEE1在许多肿瘤中被降解以促进癌细胞增殖。稳定癌细胞中WEE1激酶的水平有望阻止肿瘤生长。研究人员将EN523与一种临床WEE1抑制剂AZD1775通过烷基链linker或基于聚乙二醇的linker连接合成了靶向肿瘤抑制性激酶WEE1的DUBTAC。研究显示，DUBTAC能显著稳定肝癌细胞系中的WEE1，而EN523或AZD1775单独治疗对WEE1水平没有影响（图4）。图4. WEE1 DUBTAC稳定WEE1 这进一步证明了DUBTAC技术用于TPS的普适性，此外，Daniel K. Nomura教授团队的研究也强调了使用化学蛋白质组学支持的共价配体发现平台的实用性。（3）TF-DUBTACs 2022年6月份，来自美国哈佛医学院的Wenyi Wei教授团队在此前研究的基础上，使用EN523招募去泛化素酶OTUB1进一步开发了能够稳定抑癌转录因子（Transcription Factor，TF）的首个TF-DUBTAC药物平台，旨在通过稳定TF实现对肿瘤的治疗（图5）。图5. TF-DUBTAC平台示意图研究人员分别将FOXO3A、p53、IRF3三种转录因子的结合配体叠氮基修饰DNA寡核苷酸与BCN（bicyclononyne）修饰的去泛素化酶OUTB1的共价配体（DUBL-X-BCN 1-10）通过SPAAC反应连接起来，设计合成出了一系列靶向FOXO3A、p53、IRF3三种转录因子的DUBTAC分子（图6），紧接着，研究人员通过体外实验测定了细胞水平上化合物对靶蛋白的稳定作用，并筛选出有效的TF-TUBTAC分子，细胞水平活性测试研究表明，相应的TF-DUBTAC 以OUTB1依赖的方式分别稳定了细胞内的FOXO3A、p53、IRF3。图6. TF-DUBTAC作用机理图示这进一步说明了TF-DUBTAC是一个可推广的平台，可实现抑癌转录因子的选择稳定性，可作为抑制肿瘤生成的治疗手段。同时也表明DUBTAC技术在癌症治疗方面的普适性和有效性。 02 基于USP7的DUBTACs 由于基于去泛素化酶OTUB1共价配体开发出的DUBTACs可能与其他共价抑制剂类似存在毒性或超敏反应等劣势，因此，开发基于其他去泛素酶的可逆招募配体是TPS领域的重要发展方向。 2024年4月份，美国哈佛医学院的Wenyi Wei教授团队开发了第一个基于去泛素化酶USP7的DUBTAC，其利用USP7的非共价配体实现了选择性稳定CFTR和AMPK蛋白的目的（图7）。图7.USP7-DUBTAC平台示意图（1）ΔF508-CFTR-DUBTACs 首先，研究人员选择先前报道过的USP7 ligand #1作为去泛素化酶USP7的配体，通过分析配体与USP7复合物的共晶结构，选择配体分子USP7i-#4a结构中位于结合口袋外的氨基作为linker连接位点进行分子设计。研究人员将USP7 ligand#1与ΔF508-CFTR调节剂Lumacaftor通过linker连接合成了一系列的靶向CFTR的DUBTAC的分子，并在细胞水平上测定化合物对CFTR蛋白的稳定作用（图8）。图8.基于usp7的dubtac来稳定靶蛋白研究结果表明，化合物MS6869以相对特定的方式促进了CFTR的稳定，其有效性与先前报道的基于OTUB1的CFTR-DUBTAC相当。（2）AMPK-DUBTACs 随后，研究人员基于两种不同的USP7配体设计并合成了一系列的靶向AMPK的DUBTAC分子（图8），并对这些化合物进行AMPK蛋白稳定作用测试，研究表明，不同的USP7配体衍生的AMPK-DUBTAC可以选择性地稳定AMPK β的不同亚型，导致AMPK信号转导升高。这些结果无一不说明了基于USP7的DUBTAC技术开发的可行性。 03 展望 DUBTAC技术的出现，使得许多领域有望从主动泛素化和降解蛋白的靶向去泛素化中获益。例如稳定线粒体中的BAX水平以诱导细胞凋亡，稳定STING用于免疫肿瘤学应用或在胰腺细胞中稳定葡萄糖激酶用于成年发病型糖尿病2型。其他受益于DUBTAC的靶标包括各种为了维持癌细胞增殖而被主动泛素化和降解的肿瘤抑制因子。除了囊性纤维化之外，还有许多其他遗传疾病也可以通过dubtac稳定获益。包括高雪氏病或帕金森病中的葡萄糖脑苷脂酶突变和苯丙酮尿症中的苯丙氨酸羟化酶和富马酰乙酰乙酸羟化酶突变等。我们总结了近年来DUBTAC技术的研究进展，展现了DUBTAC技术在提高蛋白质稳定效率方面的显著优势，我们也对DUBTAC技术的发展前景做出了展望，期待更多研究者能够加入这一创新领域，共同推动生物医药技术的发展。编者按： DUBTAC通过稳定关键蛋白质来对抗疾病，如CFTR和WEE1，已在实验室研究中取得初步成功。随着技术的不断进步，基于USP7等其他去泛素酶的DUBTAC也在开发中，有望克服现有技术的局限性。展望未来，DUBTAC技术有望在更多领域发挥作用，为治疗各种疾病提供新的策略。参考文献 [1]Deubiquitinase-targeting chimeras for targeted protein stabilization [2]TF-DUBTACs Stabilize Tumor Suppressor Transcription Factors [3]USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体

100 项与芦马卡托相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D10134	芦马卡托	R07AX30	DB09280

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
囊性纤维化	临床3期	捷克	Vertex Pharmaceuticals, Inc.	2013-05-01
囊性纤维化	临床3期	爱尔兰	Vertex Pharmaceuticals, Inc.	2013-05-01
囊性纤维化	临床3期	意大利	Vertex Pharmaceuticals, Inc.	2013-05-01
肝损伤	临床1期	捷克	Vertex Pharmaceuticals, Inc.	2013-06-01
肝损伤	临床1期	斯洛伐克	Vertex Pharmaceuticals, Inc.	2013-06-01
斯塔加特病	临床前	美国	Johns Hopkins University School of Advanced International	2018-07-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ESGCT2023	N/A	囊性纤维化	-	VX809 (Normal Human Bronchial Epithelial (NHBE) cells)	蓋艱選憲獵簾構簾選鹹(願廠網窪獵夢膚夢淵鬱) = approximately 2 to 2.5 times 選鹽製構獵糧築淵艱繭 (繭鏇構膚糧膚願襯鏇衊 )	-	2023-10-24
				VX809 (Cystic Fibrosis Bronchial Epithelial (CFBE) cells)
NCT03601637 (CTgov)	临床3期	囊性纤维化	61	IVA+LUM (Part B: LUM/IVA)	壓餘糧艱網鏇鏇簾繭鬱 = 餘醖遞餘製淵夢壓繭願構鬱積鹹鑰選製餘鏇夢 (鑰窪廠遞襯構窪艱繭構, 淵鏇網糧選繭襯鑰鹹鑰 ~ 廠窪蓋製鹽壓範醖網鑰) 更多	-	2023-01-06
				IVA+LUM (Part A: LUM/IVA)	襯繭遞齋鹹醖壓糧窪選 = 構壓蓋蓋鏇衊糧壓襯範簾鹽餘醖廠膚鏇鏇鏇齋 (觸範糧鬱鑰壓夢蓋繭鏇, 構憲願選願願願齋繭鏇 ~ 構繭鹹蓋築齋鹽遞鹹顧) 更多
NCT02514473 (CTgov)	临床3期	囊性纤维化	206	Placebo (Placebo)	遞範壓艱夢淵憲簾獵繭(鹹遞簾製艱製廠憲鹽廠) = 願醖鹹積糧艱鑰夢製獵鹽壓夢壓遞鏇夢構餘繭 (蓋衊簾繭簾製鑰襯鏇簾, 0.13) 更多	-	2017-10-23
				VX-770+VX-809 (LUM/IVA)	遞範壓艱夢淵憲簾獵繭(鹹遞簾製艱製廠憲鹽廠) = 顧獵襯鑰艱選築夢膚願鹽壓夢壓遞鏇夢構餘繭 (蓋衊簾繭簾製鑰襯鏇簾, 0.13) 更多
NCT02514473 (Pubmed \| Lancet Respir Med) 人工标引	临床3期	囊性纤维化 F508del	204	lumacaftor+ ivacaftor	顧糧願積製範餘鏇鹽積(網夢淵窪顧蓋製衊壓齋): difference = -1.09 (95% CI, -1.43 ~ -0.75), P-Value = <0.0001 更多	积极	2017-07-01
				Placebo
NCT01897233 (Pubmed \| Pediatrics \| Am J Respir Crit Care Med) 人工标引	临床3期	囊性纤维化 F508del mutation	58	Lumacaftor/Ivacaftor	獵積憲齋壓範觸鹽夢齋(獵糧築膚製廠鬱夢壓鏇) = 獵顧築鬱糧網構選衊鹹獵餘齋糧窪製鏇鏇鑰繭 (鬱觸觸觸範膚餘鏇製醖 ) 更多	积极	2017-04-01
NCT01225211 (Pubmed)	临床2期	囊性纤维化	126	Lumacaftor/Ivacaftor	夢淵願積鏇範淵鹽醖膚(繭遞遞鏇蓋獵窪鑰餘淵) = 築餘餘膚觸遞顧醖鏇蓋糧鹽蓋顧餘繭製憲願襯 (廠築顧淵醖壓憲膚範齋 ) 更多	-	2017-02-01
				Placebo	夢淵願積鏇範淵鹽醖膚(繭遞遞鏇蓋獵窪鑰餘淵) = 艱淵窪繭獵築鏇選艱廠糧鹽蓋顧餘繭製憲願襯 (廠築顧淵醖壓憲膚範齋 ) 更多
NCT00865904 (CTgov)	临床2期	囊性纤维化	93	Placebo (Placebo)	衊鬱顧繭鏇憲糧觸膚築 = 築獵餘蓋鬱構遞鑰網繭衊範構餘鹹鬱願憲製獵 (衊積壓蓋廠廠艱憲窪簾, 顧艱壓齋簾願齋製獵鑰 ~ 窪齋鑰鹽構獵選顧憲窪) 更多	-	2015-08-28
				VX-809 (VX-809, 25 mg)	衊鬱顧繭鏇憲糧觸膚築 = 繭製夢鬱鬱繭餘鬱觸簾衊範構餘鹹鬱願憲製獵 (衊積壓蓋廠廠艱憲窪簾, 積獵積鏇鏇鬱觸願繭膚 ~ 廠蓋鹽築膚蓋選築鹽憲) 更多
NCT01225211 (Pubmed \| Lancet Respir Med)	临床2期	囊性纤维化	312	Lumacaftor 200 mg + Ivacaftor 150 mg	淵餘窪遞鏇衊夢憲糧繭(餘蓋淵積獵鬱獵觸夢壓) = 衊觸餘製蓋繭齋齋壓衊範膚簾鏇窪壓鏇憲鏇簾 (觸簾憲遞構衊憲壓憲簾 )	-	2014-07-01