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Small molecule inhibitors of the co-receptor neuropilin-1 共受体neuropilin-1ni的小分子抑制剂。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104523

Yu-Heng Liu , Kang-Hui Liang , Wen Zhang , Guo-Wu Rao , Quan Zheng

Neuropilin-1 (NRP-1) is a multifunctional cell surface receptor that acts as a co-receptor for vascular endothelial growth factor (VEGF), semaphorins (SEMAs), and transforming growth factor β (TGF-β), and is widely involved in various physiological and pathological processes such as neural development, angiogenesis, and immune regulation. In cancer treatment, NRP-1 has attracted extensive attention because of its key role in pathological angiogenesis, tumor immune escape, and tumor progression, and it is regarded as a potential therapeutic target for tumors. In recent years, the development of small molecule inhibitors of NRP-1 has become a new research strategy. This article reviews the research progress of small molecule inhibitors of NRP-1, classifying them into three different types of small molecules, and focuses on introducing ideas for their development, mechanisms of action, and research status. It provides guidance for the future development of small molecule inhibitors of NRP-1.

神经匹林-1 （Neuropilin-1, nlp -1）是一种多功能细胞表面受体，作为血管内皮生长因子（VEGF）、信号素（SEMAs）和转化生长因子β (TGF-β)的共受体，广泛参与神经发育、血管生成、免疫调节等多种生理病理过程。在肿瘤治疗中，NRP-1因其在病理性血管生成、肿瘤免疫逃逸、肿瘤进展等方面的关键作用而受到广泛关注，被认为是肿瘤潜在的治疗靶点。近年来，开发小分子NRP-1抑制剂已成为一种新的研究策略。本文综述了NRP-1小分子抑制剂的研究进展，将其分为三种不同类型的小分子抑制剂，重点介绍了它们的开发思路、作用机制和研究现状。为今后NRP-1小分子抑制剂的开发提供指导。

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Implementation of a data science and artificial intelligence strategy across pharmaceutical R&D: challenges and solutions 在制药研发中实施数据科学和人工智能战略：挑战和解决方案。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104527

Vincenzo Garzya , Gabriella Rustici , Tom Diethe , Peder Blomgren , Nina Mian , Jamie MacPherson , Henry Constable , Rebecca J. Port , James Weatherall

There is a growing need to apply data science (DS) and artificial intelligence (AI) (DS&AI) solutions to the pharmaceutical research and development (R&D) pipeline to remain competitive in a rapidly evolving industry. Here, we present the challenges and solutions of an operational framework toward the realisation of the potential of DS&AI in pharmaceutical R&D.

为了在快速发展的行业中保持竞争力，越来越需要将数据科学（DS）和人工智能（AI）（DS&AI）解决方案应用于制药研发（R&D）管道。在这里，我们提出了实现DS&AI在制药研发中的潜力的操作框架的挑战和解决方案。

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Therapeutic approaches to addressing drug resistance by targeting membranes and associated structures 通过靶向膜和相关结构来解决耐药性的治疗方法。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104526

Shaoqing Du , Luis Menéndez-Arias , Xueping Hu , Peng Zhan

The cell membrane has a pivotal role in cellular activities, such as substance exchange and information transmission. Its dysfunction is closely linked to numerous diseases, positioning it as a vital target for pharmacological interventions. The unique structure of the phospholipids of the membrane, along with its associated proteins, renders it an optimal target for therapeutic interventions designed to combat drug-resistant pathogens. Here, we delve into various advanced mechanisms of action associated with targeted membrane strategies. We also discuss the challenges and future prospects related to these strategies, emphasizing that the integration of various technologies into experimental practices will be a crucial direction for future development.

细胞膜在细胞活动中起着重要的作用，如物质交换和信息传递。它的功能障碍与许多疾病密切相关，使其成为药理干预的重要靶点。膜磷脂的独特结构及其相关蛋白使其成为对抗耐药病原体的治疗干预的最佳目标。在这里，我们深入研究了与靶向膜策略相关的各种高级作用机制。我们还讨论了与这些策略相关的挑战和未来前景，强调将各种技术整合到实验实践中将是未来发展的关键方向。

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The emerging role of fatty acid-binding protein 3 (FABP3) in cancer 脂肪酸结合蛋白3 （FABP3）在癌症中的新作用。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104504

William Warren, Myles Osborn, Andy Yates, Saoirse O’Sullivan

Fatty acid-binding proteins (FABPs) are intracellular transporter proteins that regulate lipid transport, signalling, and homeostasis. In this review, we assess whether upregulation of FABP3 is oncogenic. Cancers where overexpression of FABP3 was shown to be oncogenic included breast, brain, nonsmall cell lung cancer (NSCLC), gastric, melanomas, and leiomyosarcoma. FABP3 knockdown in brain, oesophageal, and melanoma cell lines reduced proliferation, migration, invasion, and colony formation in vitro, and attenuated glioma tumour burden in vivo. In tumours and the tumour immune microenvironment, the protumoral mechanisms of FABP3 are associated with hypoxia, ferroptosis, endothelial growth factor receptor resistance, and lipid metabolism. Emerging mechanisms primarily relate to its role as a chaperone of polyunsaturated fatty acids (PUFAs). Overall, FABPs appear to be promising targets for novel cancer treatments.

脂肪酸结合蛋白（FABPs）是调节脂质转运、信号传导和体内平衡的细胞内转运蛋白。在这篇综述中，我们评估了FABP3的上调是否致癌。过度表达FABP3的癌症包括乳腺癌、脑癌、非小细胞肺癌（NSCLC）、胃癌、黑色素瘤和平滑肌肉瘤。在脑、食管和黑色素瘤细胞系中，FABP3敲低可减少体外增殖、迁移、侵袭和集落形成，并减轻体内胶质瘤肿瘤负荷。在肿瘤和肿瘤免疫微环境中，FABP3的发病机制与缺氧、铁下垂、内皮生长因子受体抵抗和脂质代谢有关。新兴的机制主要与它作为多不饱和脂肪酸（PUFAs）伴侣的作用有关。总的来说，fabp似乎是新型癌症治疗的有希望的靶点。

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Advances in antibody-based strategies for targeting cancer-associated glycopeptide antigens 靶向癌症相关糖肽抗原的抗体策略研究进展。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104507

Edward P.W. Meier, Andreas H. Laustsen

The development of tumor-targeting antibodies has progressed tremendously over the past few decades, yet improving tumor selectivity and efficacy remains a challenge. Among tumor-associated antigens, tumor-associated carbohydrate antigens (TACAs) have emerged as critical immunological targets because of their overexpression in malignant cells. However, the weak immunogenicity and structural homogeneity of carbohydrates pose obstacles for therapeutic antibody development. By designing antibodies to recognize epitopes that span both TACAs and adjacent amino acid residues on tumor glycoprotein surfaces, researchers can achieve higher specificity and functional efficacy while lowering on-target off-tumor related toxicities.

在过去的几十年里，肿瘤靶向抗体的发展取得了巨大的进展，但提高肿瘤的选择性和有效性仍然是一个挑战。在肿瘤相关抗原中，肿瘤相关碳水化合物抗原（TACAs）因其在恶性细胞中的过度表达而成为重要的免疫靶点。然而，碳水化合物较弱的免疫原性和结构同质性阻碍了治疗性抗体的开发。通过设计抗体来识别跨越TACAs和肿瘤糖蛋白表面邻近氨基酸残基的表位，研究人员可以获得更高的特异性和功能功效，同时降低靶向非肿瘤相关的毒性。

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Click chemistry for natural product-inspired covalent drug discovery 点击化学获取天然产物启发的共价药物发现。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104500

Elliot Smith, Dharmendra S. Vishwakarma, Shoujun Sun, Adam D. Moorhouse, David A. Tuveson, John E. Moses

Metabolites, including primary and secondary metabolites, the latter often termed ‘natural products’ (NPs), offer a structurally rich source of scaffolds for drug discovery. Although many act through reversible binding, a notable subset exerts potent effects via covalent mechanisms, offering distinct advantages. Advances in click chemistry now enable modular incorporation of electrophilic warheads and bioorthogonal handles onto NP frameworks, facilitating the discovery of new covalent agents and the mapping of their biological activity. In this review, we highlight key classes of ‘click electrophiles’ and their integration into NP scaffolds, examine how click chemistry supports activity-based protein profiling (ABPP) of covalent NPs, and introduce clickable covalent metabolite mimetics (CoMMs) as a unifying framework for advancing inverse covalent drug discovery.

代谢物，包括初级代谢物和次级代谢物，后者通常称为“天然产物”（NPs），为药物发现提供了结构丰富的支架来源。尽管许多药物通过可逆结合发挥作用，但有一部分药物通过共价机制发挥强大的作用，具有明显的优势。点击化学的进步现在使亲电弹头和生物正交手柄模块化地结合到NP框架上，促进了新的共价剂的发现和它们的生物活性的绘制。在这篇综述中，我们重点介绍了“点击亲电试剂”的关键类别及其与NP支架的整合，研究了点击化学如何支持共价NP的基于活性的蛋白质分析（ABPP），并引入了可点击共价代谢模拟物（CoMMs）作为推进逆共价药物发现的统一框架。

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Immune and inflammatory responses in microgravity: implications and therapeutic approaches 微重力下的免疫和炎症反应：意义和治疗方法。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104503

Asmaa Ismail , Adel B. Elmoselhi , Lina Abu Nada , Betul Rahman , Zahi Badran , Elise Verron

Spaceflight exposes the human body to microgravity, isolation, and radiation, which collectively disrupt physiological homeostasis, particularly affecting the immune system. Microgravity significantly impairs both innate and adaptive immune responses by altering immune cell formation, activation, trafficking, and cytokine production. These disturbances manifest as an overall shift toward an immunosuppressive phenotype, increased oxidative stress, and transcriptional reprogramming of immune cells. Pharmacological agents, including natural antioxidants, flavonoids, and bioactive polysaccharides, have demonstrated anti-inflammatory and immune-restorative effects in microgravity models. In this review, we highlight the molecular mechanisms of immune dysfunction in microgravity and explore current potential therapeutic approaches to ensure safe long-duration space missions.

航天飞行使人体暴露在微重力、隔离和辐射中，这些因素共同破坏生理稳态，特别是影响免疫系统。微重力通过改变免疫细胞的形成、激活、运输和细胞因子的产生，显著损害先天和适应性免疫反应。这些干扰表现为免疫抑制表型的整体转变、氧化应激增加和免疫细胞的转录重编程。药物制剂，包括天然抗氧化剂、类黄酮和生物活性多糖，已经在微重力模型中显示出抗炎和免疫恢复作用。在这篇综述中，我们重点介绍了微重力下免疫功能障碍的分子机制，并探讨了目前潜在的治疗方法，以确保安全的长时间太空任务。

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Nanotherapeutics-induced pyroptosis for targeted cancer therapy: mechanistic insights and translational prospects 靶向癌症治疗的纳米疗法诱导的焦亡：机制见解和转化前景。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104521

Sayali Dighe, Sanyog Jain

Pyroptosis is an emerging immunogenic cell death pathway elicited by activated caspase and a perforating gasdermin protein. Distinctively, this mechanism manifests as pore formation, cell ballooning, and the release of intracellular content and calreticulin, thereby potentiating the immune infiltration in the tumour microenvironment (TME). Owing to its immunomodulatory function and tumour regression potential, pyroptosis has been clinically implicated in the treatment of cancer. Cutting-edge nanomedicines have empowered targeted and safer pyroptosis induction, thus diminishing the inherent pitfalls linked with traditional pyroptosis therapy. In this review, we detail the pathways of pyroptosis, therapeutic implications, and advances in nanotechnology-based pyroptosis therapy.

焦亡是一种新兴的免疫原性细胞死亡途径，由活化的半胱天甲酶和一种穿孔的气胶蛋白引起。特别的是，这种机制表现为孔隙形成、细胞膨胀、细胞内内容物和钙调钙蛋白的释放，从而增强肿瘤微环境中的免疫浸润（TME）。由于其免疫调节功能和肿瘤消退的潜力，焦亡在临床上被认为与癌症的治疗有关。尖端的纳米药物已经赋予了靶向和更安全的焦亡诱导，从而减少了与传统焦亡治疗相关的固有缺陷。在这篇综述中，我们详细介绍了焦亡的途径，治疗意义，以及纳米技术焦亡治疗的进展。

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Forecasting clinical trial success using anonymized external expert panels 使用匿名外部专家小组预测临床试验成功。

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104525

Frank S. David , R. Edward Benson , Mark Gordon , Daniel S. Mytelka

Drug developers and financial investors have substantial interest in making accurate forecasts of the probability of success (POS) of clinical trials. Current methods developed and used by pharmaceutical companies face challenges in optimizing for accuracy, freedom from bias, and scalability. We describe here an approach based on external expert panels that showed promise across all these dimensions and could be broadly applicable for many stakeholders and scenarios requiring trial-specific POS forecasts.

药物开发人员和金融投资者对准确预测临床试验的成功概率（POS）非常感兴趣。制药公司目前开发和使用的方法在优化准确性、无偏见和可扩展性方面面临挑战。我们在这里描述了一种基于外部专家小组的方法，该方法在所有这些方面都表现出了希望，并且可以广泛适用于许多利益相关者和需要特定于试验的POS预测的场景。

引用次数: 0

Therapeutic value and regulatory characteristics of breakthrough therapy drugs in the USA and China (2021–2023): a retrospective cohort study 美国和中国突破性治疗药物的治疗价值和调控特征（2021-2023）：一项回顾性队列研究

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-11-01 DOI: 10.1016/j.drudis.2025.104508

Xiangyun Mao , Haoyu Yin , Xiaoyin Bai , Aaron S. Kesselheim , Guanqiao Li

Breakthrough Therapy Designation (BTD) programs aim to expedite the development of promising treatments for serious conditions, yet their clinical implications remain uncertain. In this study, we analyzed US Food and Drug Administration (FDA) and China's National Medical Products Administration (NMPA) approvals from 2021 to 2023 and found that 25% and 17%, respectively, had received BTD before approval. These products were more likely to undergo accelerated or conditional approvals based on early-phase evidence, but many offered only limited or insufficient therapeutic value, as assessed by hazard ratio (HR) analyses and independent health technology assessment (HTA) ratings. These findings suggest that, although BTD pathways have the potential to expedite regulatory approval, they do not guarantee substantial clinical benefit, underscoring the need for a more cautious and evidence-based application of these BTD designations.

突破性疗法指定（BTD）项目旨在加速开发有希望的严重疾病治疗方法，但其临床意义仍不确定。在本研究中，我们分析了美国食品药品监督管理局（FDA）和国家药品监督管理局（NMPA）从2021年到2023年的批准，发现分别有25%和17%的药物在批准前获得了BTD。这些产品更有可能经过加速或有条件的审查，并且通常基于早期证据获得批准，但根据风险比（HR）分析和独立卫生技术评估（HTA）评级，许多产品仅提供有限或不足的治疗价值。这些发现表明，尽管BTD途径可以加快监管部门的批准，但它们并不能保证实质性的临床益处，这强调了对这些BTD命名的应用需要更加谨慎和基于证据的应用。

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