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Discovering a transformative cancer drug: the case of ibrutinib 发现一种变革性的抗癌药物：依鲁替尼的案例。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104542
Liam Bendicksen , Lawrence King , Edward R. Scheffer Cliff , Aaron S. Kesselheim
Transformative medicines have extended and improved many lives. Few studies, however, have qualitatively investigated how transformative drugs are discovered and developed. We conducted semi-structured interviews to investigate how scientists discovered ibrutinib (Imbruvica), a transformative drug for chronic lymphocytic leukemia. Ibrutinib originated as a tool compound, created to help chemists understand the effects of inhibiting Bruton tyrosine kinase to treat autoimmune diseases. After the corporate owner of ibrutinib sold it to a struggling biotech firm for very little money, the biotech reconceptualized ibrutinib as a cancer therapy. Even after ibrutinib showed preliminary signs of efficacy, internationally accepted response criteria that did not account for its novel mechanism of action threatened to derail its development and ability to reach patients.
变革性药物延长和改善了许多人的生命。然而，很少有研究定性地调查了变革性药物是如何被发现和开发的。我们进行了半结构化访谈，以调查科学家如何发现伊鲁替尼（Imbruvica），一种治疗慢性淋巴细胞白血病的变革性药物。伊鲁替尼最初是一种工具化合物，旨在帮助化学家了解抑制布鲁顿酪氨酸激酶治疗自身免疫性疾病的效果。伊鲁替尼的公司所有者以极低的价格将其出售给一家苦苦挣扎的生物技术公司后，该生物技术公司将伊鲁替尼重新定义为一种癌症治疗药物。即使在伊鲁替尼显示出初步的疗效迹象后，国际上接受的反应标准没有考虑到其新的作用机制，这可能会破坏其开发和达到患者的能力。
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引用次数: 0
A survey of the use of EHR as real-world evidence for discovering and validating new drug indications 使用电子病历作为发现和验证新药适应症的真实证据的调查。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104552
Nabasmita Talukdar , Xiaodan Zhang , Shreya Paithankar , Hui Wang , Bin Chen
Electronic health records (EHRs) have been increasingly used as real-world evidence to support the discovery and validation of new drug indications. This paper surveys current approaches to EHR-based drug repurposing, covering data sources, processing methodologies, and representation techniques. It discusses study designs and statistical frameworks for evaluating drug efficacy. Key challenges and opportunities in validation are also discussed, with an emphasis on the role of large language models and target trial emulation. By synthesizing recent developments and methodological advances, this work provides a foundational resource for researchers aiming to translate real-world data into actionable drug repurposing evidence.
电子健康记录（EHRs）已越来越多地被用作支持新药适应症的发现和验证的真实证据。本文调查了目前基于电子病历的药物再利用方法，包括数据源、处理方法和表示技术。它讨论了评估药物疗效的研究设计和统计框架。还讨论了验证中的关键挑战，重点是大型语言模型和目标试验仿真的作用。通过综合最近的发展和方法的进步，这项工作为研究人员提供了一个基础资源，旨在将现实世界的数据转化为可操作的药物再利用证据。
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引用次数: 0
Electrospun proliposomes and the quest to overcome liposome instability 电纺丝原脂质体和克服脂质体不稳定性的探索。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104548
Ruchika , Sudesh Kumar Yadav , Ankit Saneja
Electrospun proliposomes are an innovative solid-state drug delivery approach in which amphiphilic nanofibers, composed of a hydrophilic polymer, phospholipids, and therapeutic agent(s), are fabricated via electrospinning. These nanofibers stabilize lipids in a dry matrix and spontaneously self-assemble into nanoscale liposomes upon hydration. The integration of liposomes with electrospun nanofibrous scaffolds represents an innovative approach, creating a synergistic nanoscale drug delivery system that combines the complementary advantages of both liposomal and nanofiber technologies. The templating effect of nanofibers, combined with polymer carriers, enhances stability, facilitates the dispersion of therapeutic agent(s), and enables on-demand liposome formation. This opinion article highlights the principles of the in situ proliposome method and the advantages, therapeutic applications, challenges, and opportunities of electrospun proliposomes, positioning them in the broader quest to overcome liposome instability.
电纺丝原脂质体是一种创新的固态药物递送方法，其中两亲性纳米纤维由亲水聚合物、磷脂和治疗剂组成，通过电纺丝制备。这些纳米纤维在干燥的基质中稳定脂质，并在水合作用下自发地自组装成纳米级脂质体。脂质体与电纺丝纳米纤维支架的整合代表了一种创新的方法，创造了一种协同的纳米级药物输送系统，结合了脂质体和纳米纤维技术的互补优势。纳米纤维的模板效应与聚合物载体结合，增强了稳定性，促进了治疗剂的分散，并实现了按需脂质体的形成。这篇观点文章强调了原位原脂质体方法的原理，以及电纺丝原脂质体的优势、治疗应用、挑战和机遇，将它们定位在克服脂质体不稳定性的更广泛的探索中。
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引用次数: 0
Regulators of system xc−–glutathione-glutathione peroxidase 4 antioxidant pathway: Recent advances and challenges in targeting ferroptosis for cancer treatment 系统xc-谷胱甘肽-谷胱甘肽过氧化物酶4抗氧化途径的调节因子：针对铁死亡癌症治疗的最新进展和挑战。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104546
Priyanka, Subhi Gupta, Manya Vatsa, Santanu Mondal
Ferroptosis is an iron-dependent mode of cell death that is driven by phospholipid peroxides. Ferroptosis inducers (FINs) are a new paradigm in cancer treatment as several therapy-resistant cancer cells are sensitive to ferroptosis. System xc− and glutathione peroxidase 4 (GPX4) are two predominant targets of FINs. Although GPX4 inhibitors prevent the reduction of lipid peroxides, system xc− inhibitors block glutathione biosynthesis and indirectly inhibit GPX4. In this review, we provide an updated summary of GPX4 and system xc− inhibitors, as well as GPX4 degraders. We also discuss the shortcomings that impede the clinical success of these FINs for cancer treatment.
铁下垂是一种由磷脂过氧化物驱动的铁依赖性细胞死亡模式。铁下垂诱导剂（FINs）是一种新的癌症治疗模式，因为一些治疗耐药的癌细胞对铁下垂敏感。系统xc-和谷胱甘肽过氧化物酶4 （GPX4）是FINs的两个主要靶点。虽然GPX4抑制剂阻止脂质过氧化物的还原，但系统xc-抑制剂阻断谷胱甘肽的生物合成并间接抑制GPX4。在这篇综述中，我们提供了GPX4和系统xc-抑制剂以及GPX4降解剂的最新综述。我们还讨论了阻碍这些FINs用于癌症治疗的临床成功的缺点。
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引用次数: 0
Targeting viral replication complexes with mRNA-encoded nanobodies: a new frontier for antiviral design 用mrna编码的纳米体靶向病毒复制复合体：抗病毒设计的新前沿。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104531
Jeremy Blavier , Gennaro Esposito , Jean-Claude Twizere , Piergiorgio Percipalle
Emerging and re-emerging RNA viruses continue to challenge global health preparedness, underscoring the need for broad-spectrum antivirals that can be rapidly deployed. We propose a family-specific antiviral design strategy that targets conserved replication–transcription complexes (RTCs) using nanobodies delivered as mRNA therapeutics. This approach overcomes the long-standing limitation of intracellular delivery of antibody-based biologics. By expressing antiviral nanobodies directly inside infected cells via lipid-nanoparticle-encapsulated mRNA, it becomes possible to disrupt essential protein–protein interactions within viral RTCs. Using SARS-CoV-2 non-structural protein 9 (NSP9) as a proof-of-concept, we show that stabilizing non-functional NSP9 oligomers can inhibit viral replication. This combined nanobody–mRNA technology provides a versatile platform for rapid antiviral development across virus families.
新出现和再出现的RNA病毒继续对全球卫生准备工作构成挑战，强调需要能够迅速部署的广谱抗病毒药物。我们提出了一种家族特异性抗病毒设计策略，该策略使用纳米体作为mRNA疗法递送，靶向保守复制转录复合物（rtc）。这种方法克服了基于抗体的生物制剂在细胞内递送的长期限制。通过脂质纳米颗粒包裹的mRNA直接在感染细胞内表达抗病毒纳米体，可以破坏病毒rtc内必需的蛋白质-蛋白质相互作用。利用SARS-CoV-2非结构蛋白9 （NSP9）作为概念验证，我们发现稳定非功能NSP9低聚物可以抑制病毒复制。这种纳米体- mrna联合技术为跨病毒家族快速开发抗病毒药物提供了一个通用平台。
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引用次数: 0
Choosing pan-HDAC or selective HDAC inhibitors for anticancer therapy 选择泛HDAC或选择性HDAC抑制剂进行抗癌治疗。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104544
Shabir Ahmad Ganai, Mahreen Bhat, Shahid Ahmad Padder
Dysfunction of histone deacetylases (HDACs) is linked to oncogenesis and progression. The expression of classical HDACs varies across different cancers. In some cancers, isozymes of one HDAC class are overactive, whereas in others, multiple classes are involved. HDAC inhibitors (HDACi), which are promising cancer therapeutics, fine-tune the aberrant behaviour of HDACs. These inhibitors are either selective or pan-inhibitors, and it is uncertain which type is the most suitable for treatment. Herein, the optimal solution to this ambiguity is provided based on solid evidence. We suggest that the HDAC overexpression pattern in a specific cancer is key to choosing the optimal therapeutic regimen.
组蛋白去乙酰化酶（hdac）功能障碍与肿瘤的发生和进展有关。经典hdac的表达在不同的癌症中有所不同。在一些癌症中，一类HDAC同工酶过度活跃，而在另一些癌症中，涉及多种HDAC同工酶。HDAC抑制剂（HDACi）是一种很有前途的癌症治疗药物，可以微调HDAC的异常行为。这些抑制剂要么是选择性抑制剂，要么是泛抑制剂，目前还不确定哪种类型最适合治疗。在此，基于确凿的证据给出了这种模糊性的最优解。我们认为，特定癌症中的HDAC过表达模式是选择最佳治疗方案的关键。
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引用次数: 0
Membrane curvature: a key regulator of membrane protein structure and function 膜曲率：膜蛋白结构和功能的关键调节因子。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104550
Pu Jiang , Cong Zhang , Cong Lin , Yibo Wang , Xiaohui Wang
Membrane curvature is a fundamental biophysical property that regulates the spatial organization, conformation and function of membrane-associated proteins, playing a crucial part in cellular signaling, material transport and membrane remodeling. Recent advances in imaging and computational technologies have deepened our understanding of the mechanisms driving membrane curvature and its influence on membrane protein function. In this review, we explore the key determinants of membrane curvature, its influence on the structure, function, localization, aggregation and dissociation of membrane proteins, and the experimental and computational strategies employed to investigate these interactions. Additionally, we discuss the therapeutic potential of targeting membrane curvature for disease treatment and outline current challenges and future research directions.
膜曲率是调节膜相关蛋白的空间组织、构象和功能的基本生物物理特性，在细胞信号传导、物质运输和膜重塑中起着至关重要的作用。成像和计算技术的最新进展加深了我们对膜曲率驱动机制及其对膜蛋白功能的影响的理解。在这篇综述中，我们探讨了膜曲率的关键决定因素，它对膜蛋白的结构、功能、定位、聚集和解离的影响，以及用于研究这些相互作用的实验和计算策略。此外，我们讨论了靶向膜曲率治疗疾病的治疗潜力，并概述了当前的挑战和未来的研究方向。
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引用次数: 0
Therapeutic strategies for reversing cardiac fibrosis in hearts supported by ventricular assist devices 逆转心室辅助装置支持心脏纤维化的治疗策略。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104547
Kartiga Natarajan , Muthu Kumar Krishnamoorthi , Suresh S. Palaniyandi , Kenichi Watanabe , Henry J. Pownall , Ashrith Guha , Arvind Bhimaraj , Rajarajan A. Thandavarayan
Left ventricular assist devices (LVADs) support patients with end-stage heart failure, yet myocardial recovery and device explant remains rare because of persistent cardiac fibrosis. This review examines the integration of molecular mechanisms and highlights therapeutic targets emerging from clinical and preclinical studies, with a focus on mechanisms that differentiate responders from non-responders. Key pathways include extracellular matrix remodeling, fibroblast activation, cellular plasticity, endothelial-to-mesenchymal transition, immune modulation, and post-transcriptional regulation via alternative polyadenylation. Advancing these mechanistic insights could enable biomarker-driven strategies to overcome the current barriers to improving recovery rates in patients supported by LVADs.
左心室辅助装置（lvad）支持终末期心力衰竭患者，但由于持续的心脏纤维化，心肌恢复和设备移植仍然很少。这篇综述探讨了分子机制的整合，并强调了临床和临床前研究中出现的治疗靶点，重点是区分反应者和无反应者的机制。关键通路包括细胞外基质重塑、成纤维细胞活化、细胞可塑性、内皮细胞向间质细胞转化、免疫调节以及通过选择性聚腺苷化介导的转录后调节。推进这些机制的见解可以使生物标志物驱动的策略克服目前在lvad支持下提高患者康复率的障碍。
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引用次数: 0
The value proposition in clinical trials: a framework for drug development 临床试验的价值主张：药物开发的框架。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104545
Christopher D. Breder
Value can be introduced into the clinical drug development process by increasing the probability of success, and through product differentiation. Quality-by-design tools, expected in formulation optimization, are not common in trial design and program optimization. In this paper, I spotlight recent efforts to incorporate these methods and make suggestions for value-driven clinical development. Value-driven product development is introduced by noting the earlier history outside the pharmaceutical sector. A description of innovations in trial design and program structure highlights the recent focus on inserting value into the drug development process. Shrewdly designed trials can provide higher-quality data with fewer subjects and resources, a timelier basis, and more value for companies. There is a value in planning: plan for value.
价值可以通过增加成功的概率，并通过产品差异化引入临床药物开发过程。在配方优化中使用的设计质量工具在试验设计和程序优化中并不常见。在本文中，我重点介绍了最近将这些方法结合起来的努力，并为价值驱动的临床开发提出了建议。通过注意制药部门以外的早期历史，介绍了价值驱动的产品开发。对试验设计和项目结构的创新的描述突出了最近对将价值插入药物开发过程的关注。精心设计的试验可以用更少的受试者和资源、更及时的基础提供更高质量的数据，并为公司带来更多价值。计划是有价值的：为价值而计划。
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引用次数: 0
Advances in copper complexes in cancer treatment 铜配合物在癌症治疗中的研究进展。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-01 DOI: 10.1016/j.drudis.2025.104522
Lucía M. Balsa , Lucía Santa Maria de la Parra , Olivia Espindola-Moreno , Ignacio E. León
Copper complexes are a class of anticancer compounds studied for the treatment of various types of solid tumors, such as breast, lung, bone, prostate, and ovarian tumors, among others. These compounds have several effects on tumor cell death mechanisms, including apoptosis, necrosis, ferroptosis, and cuproptosis. The chemistry and anticancer activity of copper-based complexes are summarized in this review based on preclinical and clinical research that focuses on structure–activity relationships, molecular targets, and investigation of the mechanism of action and cell death underlying their anticancer activity.
铜配合物是研究用于治疗乳腺、肺、骨、前列腺、卵巢等多种实体肿瘤的抗癌化合物。这些化合物对肿瘤细胞死亡机制有多种影响，包括凋亡、坏死、铁下垂和铜下垂。本文综述了铜基配合物的化学和抗癌活性的临床前和临床研究，重点介绍了其结构-活性关系、分子靶点、作用机制和细胞死亡机制的研究。
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引用次数: 0
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