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Building a human genetic data lake to scale up insights for drug discovery 建立人类基因数据湖，以扩大对药物发现的见解。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-06-01 DOI: 10.1016/j.drudis.2025.104385
Clement Chatelain , Samuel Lessard , Katherine Klinger , Shameer Khader , Emanuele de Rinaldis
{"title":"Building a human genetic data lake to scale up insights for drug discovery","authors":"Clement Chatelain ,&nbsp;Samuel Lessard ,&nbsp;Katherine Klinger ,&nbsp;Shameer Khader ,&nbsp;Emanuele de Rinaldis","doi":"10.1016/j.drudis.2025.104385","DOIUrl":"10.1016/j.drudis.2025.104385","url":null,"abstract":"<div><div>Genome-wide association studies (GWAS) have identified numerous disease-associated variants, yet efficient storage and analysis of genetic data remain a challenge. Here, we propose a scalable genetic data lake (GDL) integrating GWAS, molecular quantitative trait loci (mQTL), and epigenetic data within a big data infrastructure to enable rapid analysis. This framework allows large-scale computations, prioritizing 54 586 gene–trait associations, including 34 779 found exclusively in consortium data sets. By leveraging public, consortium, and private data, this approach enhances target discovery and indication selection, accelerating drug development.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 6","pages":"Article 104385"},"PeriodicalIF":6.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic potential of acetyl-DL-leucine and its L-enantiomer in posterior fossa syndrome: Mechanistic insights 乙酰- dl -亮氨酸及其l-对映体治疗后窝综合征的潜力：机制见解。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-06-01 DOI: 10.1016/j.drudis.2025.104389
Přemysl Vlček , Jiří Horáček , Marcela Grünerová-Lippertová , Martin Brunovský
{"title":"Therapeutic potential of acetyl-DL-leucine and its L-enantiomer in posterior fossa syndrome: Mechanistic insights","authors":"Přemysl Vlček ,&nbsp;Jiří Horáček ,&nbsp;Marcela Grünerová-Lippertová ,&nbsp;Martin Brunovský","doi":"10.1016/j.drudis.2025.104389","DOIUrl":"10.1016/j.drudis.2025.104389","url":null,"abstract":"<div><div>Posterior fossa syndrome (PFS) is a serious postoperative complication that primarily affects children following resection of posterior fossa tumors. Although its complex pathophysiology, involving disruption of cerebellar structures and the dentato–thalamo-cortical pathway, is increasingly being elucidated, effective treatments remain limited. This perspective explores acetyl-DL-leucine (ADLL) and its active L-enantiomer, N-acetyl-L-leucine (NALL), as promising therapeutic candidates for PFS. Emerging mechanistic, preclinical, and clinical evidence suggests that both compounds might alleviate PFS symptoms through neuroprotective and neurorestorative mechanisms, including neuronal membrane stabilization, metabolic enhancement, antioxidant and anti-inflammatory effects, and dopaminergic modulation. NALL, which has greater neurotherapeutic potential than ADLL, might particularly support recovery through its multimodal effects on neuronal function, thereby enhancing perioperative resilience. Further translational research into these acetylated leucine analogues is warranted.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 6","pages":"Article 104389"},"PeriodicalIF":6.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Insights from the European Medicines Agency on digital health technology derived endpoints 来自欧洲药品管理局关于数字医疗技术衍生端点的见解。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-06-01 DOI: 10.1016/j.drudis.2025.104388
Keerti D. Jadoenathmisier , Helga Gardarsdottir , Peter G.M. Mol , Anna M.G. Pasmooij
{"title":"Insights from the European Medicines Agency on digital health technology derived endpoints","authors":"Keerti D. Jadoenathmisier ,&nbsp;Helga Gardarsdottir ,&nbsp;Peter G.M. Mol ,&nbsp;Anna M.G. Pasmooij","doi":"10.1016/j.drudis.2025.104388","DOIUrl":"10.1016/j.drudis.2025.104388","url":null,"abstract":"<div><div>This study evaluates the use of digital health technologies (DHTs) for endpoint measurement in clinical trials, as documented in the Qualification Opinions, Qualification Advice, and Scientific Advice procedures issued by the European Medicines Agency (EMA) between 2013 and 2022. Accelerometers are the most proposed DHTs, followed by glucose monitors and smartphones. Accelerometers are often proposed for nervous system diseases to support mobility measures and objective testing. Most DHTs were proposed for efficacy endpoints. The feedback provided by EMA emphasizes the importance of validation, precision, and a clearly defined context of use. The EMA’s recent action plan further supports advancing DHT methodologies in clinical trials.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 6","pages":"Article 104388"},"PeriodicalIF":6.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Navigating the complexities of spinal cord injury: an overview of pathology, treatment strategies and clinical trials 导航脊髓损伤的复杂性：病理学，治疗策略和临床试验的概述。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-06-01 DOI: 10.1016/j.drudis.2025.104387
Manjeet Chopra, Hemant Kumar
{"title":"Navigating the complexities of spinal cord injury: an overview of pathology, treatment strategies and clinical trials","authors":"Manjeet Chopra,&nbsp;Hemant Kumar","doi":"10.1016/j.drudis.2025.104387","DOIUrl":"10.1016/j.drudis.2025.104387","url":null,"abstract":"<div><div>Spinal cord injury (SCI) is a debilitating neurological condition characterized by sensory and motor deficits. It significantly affects patient quality of life and poses a substantial socioeconomic burden. The complex and multifaceted pathophysiology of SCI complicates its effective treatment. Following the primary mechanical insult, a secondary injury cascade disrupts the microenvironment at the injury site, exacerbating the tissue damage. Despite extensive research, no fully effective treatment is currently available. This review explores current pharmacological and non-pharmacological treatment strategies at the preclinical and clinical stages, providing insights into promising interventions. The findings highlight potential avenues for future research aimed at improving SCI management.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 6","pages":"Article 104387"},"PeriodicalIF":6.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chemical space visual navigation in the era of deep learning and Big Data. 深度学习和大数据时代的化学空间视觉导航。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-05-31 DOI: 10.1016/j.drudis.2025.104392
Sergey Sosnin
{"title":"Chemical space visual navigation in the era of deep learning and Big Data.","authors":"Sergey Sosnin","doi":"10.1016/j.drudis.2025.104392","DOIUrl":"https://doi.org/10.1016/j.drudis.2025.104392","url":null,"abstract":"<p><p>The 'Big Data' era in medicinal chemistry presents new challenges for analysis. While modern computers can store and process millions of molecular structures, final decisions in medicinal chemistry remain in human hands. However, the ability of humans to analyze large chemical data sets is limited by cognitive constraints, creating a demand for methods and tools to visualize chemical space. In this review, I highlight recent advances in algorithms and tools for visual navigation in chemical space. I explore how these methods are evolving to address the 'Big Data' challenge and discuss unconventional applications, including the visual validation of quantitative structure-activity relationship (QSAR)/quantitative structure-property relationship (QSPR) models, interactive generative approaches, and even the use of chemical space maps as digital art.</p>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104392"},"PeriodicalIF":6.5,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
AI-driven approaches in therapeutic interventions: Transforming RNA-seq analysis into biomarker discovery and drug development. 人工智能驱动的治疗干预方法：将RNA-seq分析转化为生物标志物发现和药物开发。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-05-29 DOI: 10.1016/j.drudis.2025.104391
Zehra, Anam Bakhtiyar, Asimul Islam, Romana Ishrat, Md Imtaiyaz Hassan
{"title":"AI-driven approaches in therapeutic interventions: Transforming RNA-seq analysis into biomarker discovery and drug development.","authors":"Zehra, Anam Bakhtiyar, Asimul Islam, Romana Ishrat, Md Imtaiyaz Hassan","doi":"10.1016/j.drudis.2025.104391","DOIUrl":"https://doi.org/10.1016/j.drudis.2025.104391","url":null,"abstract":"<p><p>Pharmacotranscriptomics integrates transcriptomics and pharmacology to discover potential therapeutic targets for effective treatment. This review focuses on significant advancements in combining artificial intelligence (AI) with transcriptomic research, enabling the conversion of vast data sets into valuable knowledge for therapeutics. We provide detailed insights into implementing machine learning (ML) techniques for analyzing intricate transcriptomic data, facilitating a comprehensive understanding of disease mechanisms and the identification of key signature genes for biomarker and drug development. We further highlight the potential of ML to streamline the drug discovery process by revealing disease mechanisms and suggesting therapeutic interventions. This review presents a framework of AI models and their applications within pharmacotranscriptomics analysis. We also discuss the challenges and limitations needed to optimize AI models for enhanced therapeutic outcomes.</p>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104391"},"PeriodicalIF":6.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic innovation in drug repurposing: Challenges and opportunities. 药物再利用中的治疗创新：挑战与机遇。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-05-27 DOI: 10.1016/j.drudis.2025.104390
Asha Recino, Melissa L D Rayner, Jennifer L Rohn, Oscar Della Pasqua
{"title":"Therapeutic innovation in drug repurposing: Challenges and opportunities.","authors":"Asha Recino, Melissa L D Rayner, Jennifer L Rohn, Oscar Della Pasqua","doi":"10.1016/j.drudis.2025.104390","DOIUrl":"10.1016/j.drudis.2025.104390","url":null,"abstract":"<p><p>Drug repurposing leverages existing drugs for new therapeutic uses, offering significant opportunities but facing challenges such as financial and regulatory barriers and the need for robust evidence for an efficient clinical development plan. This paper examines the critical steps in drug repurposing and their role in improving study success rates. It also highlights the support infrastructure provided by the University College London (UCL) Repurposing Therapeutic Innovation Network (TIN), as a partnership model to address these challenges through diverse expertise, enterprise insight, and tailored guidance. By fostering collaborations and offering structured support, the Repurposing TIN aims to accelerate repurposing efforts and deliver patient benefits. We invite potential collaborators to join us in advancing drug repurposing through innovative and strategic approaches.</p>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104390"},"PeriodicalIF":6.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A review of the efficacy of prostate cancer therapies against castration-resistant prostate cancer 前列腺癌治疗去势抵抗性前列腺癌的疗效综述。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-05-21 DOI: 10.1016/j.drudis.2025.104384
Shengxin Zhang, Tao Zhang, Gemma K. Kinsella, James F. Curtin
{"title":"A review of the efficacy of prostate cancer therapies against castration-resistant prostate cancer","authors":"Shengxin Zhang,&nbsp;Tao Zhang,&nbsp;Gemma K. Kinsella,&nbsp;James F. Curtin","doi":"10.1016/j.drudis.2025.104384","DOIUrl":"10.1016/j.drudis.2025.104384","url":null,"abstract":"<div><div>The standard treatments for prostate cancer (PCa) include chemotherapy, hormone therapy, targeted therapies based on androgen receptor (AR) and/or gonadotropin-releasing hormone (GnRH) receptor antagonists, and radiation therapy. But PCa therapeutic resistance remains an unsolved challenge, leading to progression to castration-resistant prostate cancer (CRPC). Emerging PCa therapies – including poly(ADP-ribose) polymerase (PARP) inhibitors, AR crosstalk signalling pathway inhibitors, B-cell lymphoma 2 (BCL-2) inhibitors, cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitors, CRISPR/Cas9, epigenetic inhibitors, and nanotechnology-based drug-delivery approaches – provide promising targeted solutions. Targeted protein degradation therapy, particularly AR degradation therapies, effectively inhibits resistance at its source. This review summarises the established and emerging PCa therapies, focusing on discussing their efficacy in terms of PCa resistance with supporting experimental findings and the mechanisms of PCa drug resistance.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 6","pages":"Article 104384"},"PeriodicalIF":6.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effectiveness of histamine receptor antagonists in the treatment of histamine-driven clinical symptoms: do we have a histamine or, better, an anti-histamine problem? 组胺受体拮抗剂在治疗组胺驱动的临床症状中的有效性：我们是否有组胺或更好的抗组胺问题？
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-05-21 DOI: 10.1016/j.drudis.2025.104383
Thomas Boehm, Bernd Jilma
{"title":"Effectiveness of histamine receptor antagonists in the treatment of histamine-driven clinical symptoms: do we have a histamine or, better, an anti-histamine problem?","authors":"Thomas Boehm,&nbsp;Bernd Jilma","doi":"10.1016/j.drudis.2025.104383","DOIUrl":"10.1016/j.drudis.2025.104383","url":null,"abstract":"<div><div>Why are up to 50% of patients with chronic urticaria resistant to antihistamines? Why do many patients with indolent systemic mastocytosis suffer severe symptoms despite treatment with four times the approved antihistamine doses? Do millions of patients with atopic diseases and related disorders have a histamine or, better, an antihistamine problem? If one carefully analyzes human clinical studies with exogenous histamine challenge and endogenous mast cell activation with prophylactic antihistamine pretreatment, the assumed efficacy of antihistamines rapidly fades. Local tissue free drug concentrations of many antihistamines are &lt;100 nM compared with 10–1000 µM possible extracellular local histamine concentrations after mast cell activation. Is the pharmaceutical industry aware of this problem?</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 6","pages":"Article 104383"},"PeriodicalIF":6.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fexaramine as the intestine-specific farnesoid X receptor agonist: A promising agent to treat obesity and metabolic disorders Fexaramine作为肠道特异性farnesoid X受体激动剂：一种治疗肥胖和代谢紊乱的有前景的药物。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-05-21 DOI: 10.1016/j.drudis.2025.104386
Anna Maria Dąbrowska , Jarosław Dudka
{"title":"Fexaramine as the intestine-specific farnesoid X receptor agonist: A promising agent to treat obesity and metabolic disorders","authors":"Anna Maria Dąbrowska ,&nbsp;Jarosław Dudka","doi":"10.1016/j.drudis.2025.104386","DOIUrl":"10.1016/j.drudis.2025.104386","url":null,"abstract":"<div><div>Fexaramine, a gut-restricted farnesoid X receptor (FXR) agonist, promotes glucose and lipid homeostasis, improves insulin sensitivity, promotes white adipose tissue browning, and stimulates nonshivering thermogenesis. Enhancement in energy expenditure due to an increase in amount of energy burned by brown and ‘beige’ adipocytes results in subsequent weight loss. Fexaramine is poorly absorbed into circulation when delivered orally, which limits systemic FXR activation and toxicity. An increase in β3-adrenoceptor signaling, activation of Takeda G protein-coupled receptor 5/glucagon-like peptide-1 (TGR5/GLP-1) signaling, and induction of fibroblast growth factor (FGF)-19/FGF-15 play crucial roles in fexaramine metabolic actions. Intestinal FXR activation is a promising, potentially safe approach for treating obesity and metabolic syndrome.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 6","pages":"Article 104386"},"PeriodicalIF":6.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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