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Death ligand receptor (DLR) signaling: Its non-apoptotic functions in cancer and the consequences of DLR-directed therapies
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104299
Khalid Rashid , Holger Kalthoff , Sarki A. Abdulkadir , Dieter Adam
{"title":"Death ligand receptor (DLR) signaling: Its non-apoptotic functions in cancer and the consequences of DLR-directed therapies","authors":"Khalid Rashid ,&nbsp;Holger Kalthoff ,&nbsp;Sarki A. Abdulkadir ,&nbsp;Dieter Adam","doi":"10.1016/j.drudis.2025.104299","DOIUrl":"10.1016/j.drudis.2025.104299","url":null,"abstract":"<div><div>Death ligands (DLs), particularly tumor necrosis factor alpha (TNF-α), FAS ligand (FASL), and TNF-related apoptosis-inducing ligand (TRAIL), collectively termed TFT, are pivotal members of the TNF superfamily. While traditionally linked to apoptosis, TFT proteins have emerged as key regulators of various non-apoptotic processes. This review summarizes the non-apoptotic functions of TFT in cancer and explores the intricate crosstalk signaling pathways and their impact on nuclear factor kappa B (NF-κB) signaling, inflammation, and pro-tumorigenic function. It also highlights the potential connections and hurdles that exist in translating synthetic lethality strategies involving DLs into clinical applications. Lastly, it discusses the challenges and opportunities associated with TFT-targeted therapeutic strategies for both malignant and non-malignant diseases.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104299"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021440","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
The impact of operational trial approaches on representativeness: Comparison of decentralized clinical trial participants, conventional trial participants, and patients in daily practice
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104304
Amos J. de Jong , Mira G.P. Zuidgeest , Yared Santa-Ana-Tellez , Christine E. Hallgreen , Thomas T. van Sloten , Anthonius de Boer , Helga Gardarsdottir , the Trials@Home Consortium
{"title":"The impact of operational trial approaches on representativeness: Comparison of decentralized clinical trial participants, conventional trial participants, and patients in daily practice","authors":"Amos J. de Jong ,&nbsp;Mira G.P. Zuidgeest ,&nbsp;Yared Santa-Ana-Tellez ,&nbsp;Christine E. Hallgreen ,&nbsp;Thomas T. van Sloten ,&nbsp;Anthonius de Boer ,&nbsp;Helga Gardarsdottir ,&nbsp;the Trials@Home Consortium","doi":"10.1016/j.drudis.2025.104304","DOIUrl":"10.1016/j.drudis.2025.104304","url":null,"abstract":"<div><div>Decentralized clinical trial (DCT) approaches – in which trial activities are conducted at participants’ homes – have the potential to improve representativeness. We present a study that compared the demographics and cardiovascular risk factors of participants from a DCT (ASCEND) and a conventional trial with a similar trial objective (POPADAD) to those of patients in daily practice. We adjudicate that there are relevant differences when comparing the participants of the conventional trial and the DCT, with the latter providing better representativeness in terms of age, insulin use, smoking status, and body mass index, whereas conventional trial participants were more representative in terms of biological sex. Differences in these characteristics were not explained by the eligibility criteria, but are considered attributable to the operational trial approach.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104304"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Applications and emerging challenges of single-cell RNA sequencing technology in tumor drug discovery 单细胞RNA测序技术在肿瘤药物发现中的应用和新挑战。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104290
Lu Zhang , Yueying Yang , Jianjun Tan
{"title":"Applications and emerging challenges of single-cell RNA sequencing technology in tumor drug discovery","authors":"Lu Zhang ,&nbsp;Yueying Yang ,&nbsp;Jianjun Tan","doi":"10.1016/j.drudis.2025.104290","DOIUrl":"10.1016/j.drudis.2025.104290","url":null,"abstract":"<div><div>Current therapeutic drugs are inadequate for curing tumors, highlighting the need for novel tumor drugs. The advancement of single-cell RNA sequencing (scRNA-seq) technology offers new opportunities for tumor drug discovery. This technology allows us to explore tumor heterogeneity and developmental mechanisms at the single-cell level. In this review, we outline the application of scRNA-seq in tumor drug discovery stages, including elucidating tumor mechanisms, identifying targets, screening drugs, and understanding drug action and resistance. We also discuss the challenges and future prospects of using scRNA-seq in drug development, providing a scientific foundation for advancing tumor therapies.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104290"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997219","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
Artificial intelligence in peptide-based drug design
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104300
Silong Zhai , Tiantao Liu , Shaolong Lin , Dan Li , Huanxiang Liu , Xiaojun Yao , Tingjun Hou
{"title":"Artificial intelligence in peptide-based drug design","authors":"Silong Zhai ,&nbsp;Tiantao Liu ,&nbsp;Shaolong Lin ,&nbsp;Dan Li ,&nbsp;Huanxiang Liu ,&nbsp;Xiaojun Yao ,&nbsp;Tingjun Hou","doi":"10.1016/j.drudis.2025.104300","DOIUrl":"10.1016/j.drudis.2025.104300","url":null,"abstract":"<div><div>Protein–protein interactions (PPIs) are fundamental to a variety of biological processes, but targeting them with small molecules is challenging because of their large and complex interaction interfaces. However, peptides have emerged as highly promising modulators of PPIs, because they can bind to protein surfaces with high affinity and specificity. Nonetheless, computational peptide design remains difficult, hindered by the intrinsic flexibility of peptides and the substantial computational resources required. Recent advances in artificial intelligence (AI) are paving new paths for peptide-based drug design. In this review, we explore the advanced deep generative models for designing target-specific peptide binders, highlight key challenges, and offer insights into the future direction of this rapidly evolving field.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104300"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021436","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
Philanthropic drug development: understanding its importance, mechanisms, and future prospects
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104298
Marc Reichel , Eva M. Murauer , Martin Steiner , Christoph Coch , Hubert Trübel
{"title":"Philanthropic drug development: understanding its importance, mechanisms, and future prospects","authors":"Marc Reichel ,&nbsp;Eva M. Murauer ,&nbsp;Martin Steiner ,&nbsp;Christoph Coch ,&nbsp;Hubert Trübel","doi":"10.1016/j.drudis.2025.104298","DOIUrl":"10.1016/j.drudis.2025.104298","url":null,"abstract":"<div><div>Philanthropic drug development (PDD) addresses gaps in traditional pharmaceutical innovation, particularly for rare and underserved diseases. Cost and timeline challenges discourage new investments, especially in niche therapeutic areas. Patient organizations (POs) are uniquely positioned to help to reduce development challenges by providing expertise, supporting early research, fostering collaborations, and driving patient-centered clinical trials. PDD relies on effective partnerships between POs, pharmaceutical companies, and other stakeholders, ensuring that patient perspectives inform the drug development process. PDD is poised to relieve the pressure on the traditional drug development process and thereby foster beneficial patient-focused innovations. In doing so, PDD allows pharmaceutical companies to expand their drug development activities into commercially unrewarding {} areas, diversifying their portfolios beyond competitive fields.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104298"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A case study assessing the impact of M&A and licensing on FDA drug approvals of leading pharmaceutical companies 一项案例研究，评估并购和许可对美国食品及药物管理局批准领先制药公司药品的影响。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104306
Alexander Schuhmacher , Kyrylo Grinchenko , Oliver Gassmann , Dominik Hartl , Markus Hinder
{"title":"A case study assessing the impact of M&A and licensing on FDA drug approvals of leading pharmaceutical companies","authors":"Alexander Schuhmacher ,&nbsp;Kyrylo Grinchenko ,&nbsp;Oliver Gassmann ,&nbsp;Dominik Hartl ,&nbsp;Markus Hinder","doi":"10.1016/j.drudis.2025.104306","DOIUrl":"10.1016/j.drudis.2025.104306","url":null,"abstract":"<div><div>Despite a recent increase in FDA new drug approvals, leading pharmaceutical companies continue to face R&amp;D productivity challenges. This highlights the need to better understand the context of their R&amp;D concepts and related R&amp;D outputs. Consequently, we conducted a systematic assessment of the impact of R&amp;D expenditures, R&amp;D intensities, mergers &amp; acquisitions (M&amp;A) deals and licensing agreements on new drug approvals of leading pharmaceutical companies between 2012 and 2021. Our analysis provides key insights into differentiating R&amp;D factors: whereas R&amp;D expenditures and the number of M&amp;A deals correlate with the number of new drug approvals, our analysis shows no correlation with R&amp;D intensity or the number of licensing agreements.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104306"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Modulating the phosphorylation status of target proteins through bifunctional molecules
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104307
Qindi He , Zhijie Wang , Rongrong Wang , Tao Lu , Yadong Chen , Shuai Lu
{"title":"Modulating the phosphorylation status of target proteins through bifunctional molecules","authors":"Qindi He ,&nbsp;Zhijie Wang ,&nbsp;Rongrong Wang ,&nbsp;Tao Lu ,&nbsp;Yadong Chen ,&nbsp;Shuai Lu","doi":"10.1016/j.drudis.2025.104307","DOIUrl":"10.1016/j.drudis.2025.104307","url":null,"abstract":"<div><div>Phosphorylation is an important form of protein post-translational modification (PTM) in cells. Dysregulation of phosphorylation is closely associated with many diseases. Because the regulation of proteins of interest (POIs) by chemically induced proximity (CIP) strategies has been widely validated, regulating the phosphorylation status of POIs by phosphorylation-regulating bifunctional molecules (PBMs) emerges as an alternative paradigm. PBMs promote the spatial proximity of POIs to kinases/phosphatases, and thus alter the phosphorylation state of POIs. Herein, we describe the history and current status of PBMs, analyze in detail the general design principles and specific applications of PBMs, assess their current advantages, possible challenges and limitations, and propose future directions for PBMs, which will stimulate interest in PBM research.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104307"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121677","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
Competition of regulatory ecosystems in approving medicines: policy implications in the case of Europe 审批药品时监管生态系统的竞争：对欧洲的政策影响。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104295
Pedro Franco , Stefan Haefliger
{"title":"Competition of regulatory ecosystems in approving medicines: policy implications in the case of Europe","authors":"Pedro Franco ,&nbsp;Stefan Haefliger","doi":"10.1016/j.drudis.2025.104295","DOIUrl":"10.1016/j.drudis.2025.104295","url":null,"abstract":"<div><div>The competition between business ecosystems is relevant not only for strategic management, but also for health policy and regulators. Regulation is one key factor in ecosystem competition, and government and regulatory bodies implement new pharmaceutical legislations, policies, and guidelines contributing to business environments capable of attracting startups, biotech firms, and pharmaceutical industry investments in innovative medicines and technologies. Implications for patients and societal welfare require a thorough analysis of strategies aimed at enhancing the competitive advantage of the European Union (EU) in attracting pharmaceutical companies to prioritize the submission of their innovative medicines. This analysis is essential for ensuring that patients have timely access to new treatments, that society benefits from advances in healthcare, and could foster the competitive advantage of the European regulatory ecosystem. Here, we present data from 47 interviews with pharmaceutical industry professionals, offering direct insights into regulatory ecosystem competition and global health policy. Our report underscores the necessity for effective strategies that enhance the competitive advantage of the European regulatory system.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104295"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997220","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
The epigenetic impact of fatty acids as DNA methylation modulators 脂肪酸作为DNA甲基化调节剂的表观遗传影响。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2024.104277
Meran Keshawa Ediriweera , W.M. Gayashani Sandamalika
{"title":"The epigenetic impact of fatty acids as DNA methylation modulators","authors":"Meran Keshawa Ediriweera ,&nbsp;W.M. Gayashani Sandamalika","doi":"10.1016/j.drudis.2024.104277","DOIUrl":"10.1016/j.drudis.2024.104277","url":null,"abstract":"<div><div>DNA methylation is a key epigenetic mechanism that regulates gene expression. Fatty acids, the building blocks of many essential lipids, play a crucial role in various biological events. Aberrant acetylation and methylation profiles are linked to a number of non-communicable diseases. Various fatty acids have been identified as potential ‘epi-drugs’ because of their ability to correct aberrant acetylation and methylation profiles in a number of non-communicable diseases, enhancing the value of their biochemical properties. This review summarizes the effects of selected saturated and unsaturated fatty acids and fatty-acid-rich food items on disease-associated DNA methylation profiles, aiming to justify the classification of fatty acids as DNA methylation modulators.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104277"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875670","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
Albendazole-induced liver injury in children: a cause for concern? 阿苯达唑致儿童肝损伤：值得关注的原因？
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104296
Devaraj Ezhilarasan, Mustapha Najimi
{"title":"Albendazole-induced liver injury in children: a cause for concern?","authors":"Devaraj Ezhilarasan,&nbsp;Mustapha Najimi","doi":"10.1016/j.drudis.2025.104296","DOIUrl":"10.1016/j.drudis.2025.104296","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 2","pages":"Article 104296"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997027","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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