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Development of LRRK2 inhibitors through computational strategies: a promising avenue for Parkinson’s disease 通过计算策略开发LRRK2抑制剂：帕金森病的有希望的途径
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-05 DOI: 10.1016/j.drudis.2025.104446
Xiaoqing Gong , Shuoyan Tan , Yuwei Yang , Yang Yu , Xiaojun Yao , Huanxiang Liu
{"title":"Development of LRRK2 inhibitors through computational strategies: a promising avenue for Parkinson’s disease","authors":"Xiaoqing Gong ,&nbsp;Shuoyan Tan ,&nbsp;Yuwei Yang ,&nbsp;Yang Yu ,&nbsp;Xiaojun Yao ,&nbsp;Huanxiang Liu","doi":"10.1016/j.drudis.2025.104446","DOIUrl":"10.1016/j.drudis.2025.104446","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that remains incurable. Leucine-rich repeat kinase 2 (LRRK2) has a pivotal role in PD pathogenesis, making it a promising therapeutic target. Thus, there is an urgent need to develop structurally diverse, highly selective, blood–brain barrier (BBB)-permeable LRRK2 inhibitors. Computer-aided and artificial intelligence (AI)-driven drug design methods have shown significant advantages in the discovery of LRRK2 inhibitors. Building upon a systematic review of structural characteristics, biological functions, and molecular mechanisms of LRRK2, in this review, we summarize recent advances in LRRK2 inhibitor development, highlighting the pivotal role of computational approaches in accelerating inhibitor discovery.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104446"},"PeriodicalIF":7.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793069","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
Learning from the EMA experience: common CMC deficiencies in marketing authorisation applications over the past decade 从EMA的经验中学习：过去十年中上市许可申请中常见的CMC缺陷。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-05 DOI: 10.1016/j.drudis.2025.104444
Dolores Hernán Pérez de la Ossa, Friederike Haas, Robert N. Bream, Evangelos Kotzagiorgis, Klara Tiitso, Veronika Jekerle
{"title":"Learning from the EMA experience: common CMC deficiencies in marketing authorisation applications over the past decade","authors":"Dolores Hernán Pérez de la Ossa,&nbsp;Friederike Haas,&nbsp;Robert N. Bream,&nbsp;Evangelos Kotzagiorgis,&nbsp;Klara Tiitso,&nbsp;Veronika Jekerle","doi":"10.1016/j.drudis.2025.104444","DOIUrl":"10.1016/j.drudis.2025.104444","url":null,"abstract":"<div><div>Here, we present an analysis of major objections (MOs) raised on quality aspects during review of marketing authorisation applications (MAAs) for new medicines via the centralised procedure in the European Union (EU). The review covers a 10-year period by analysing data from 2013, 2018, and 2023. We identify common deficiencies, which should help developers prepare dossiers aligned with EU and global standards and avoid delays to approval of medicines, thereby improving patient access to medicines. The most common deficiencies are correlated with specific product types, recent public health crises, new legal frameworks, and the publication or revision of guidance.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104444"},"PeriodicalIF":7.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774424","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
Beyond Antibodies: Reinventing Alzheimer’s Treatment for the Next Decade 超越抗体：重塑阿尔茨海默病治疗的下一个十年。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-05 DOI: 10.1016/j.drudis.2025.104445
Sabrina Garbo , Alessia Raucci , Clemens Zwergel , Jadwiga Handzlik , Cecilia Battistelli
{"title":"Beyond Antibodies: Reinventing Alzheimer’s Treatment for the Next Decade","authors":"Sabrina Garbo ,&nbsp;Alessia Raucci ,&nbsp;Clemens Zwergel ,&nbsp;Jadwiga Handzlik ,&nbsp;Cecilia Battistelli","doi":"10.1016/j.drudis.2025.104445","DOIUrl":"10.1016/j.drudis.2025.104445","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104445"},"PeriodicalIF":7.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787870","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
Long-acting drug delivery systems: Current landscape and future prospects 长效给药系统：现状与未来展望。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-05 DOI: 10.1016/j.drudis.2025.104447
Eneko Larrañeta , Juan Domínguez-Robles
{"title":"Long-acting drug delivery systems: Current landscape and future prospects","authors":"Eneko Larrañeta ,&nbsp;Juan Domínguez-Robles","doi":"10.1016/j.drudis.2025.104447","DOIUrl":"10.1016/j.drudis.2025.104447","url":null,"abstract":"<div><div>Conventional drug delivery often leads to fluctuating drug levels and reduced efficacy, especially in chronic conditions requiring sustained treatment. Long-acting drug delivery systems (LADDS) offer controlled, extended release, improving efficacy, safety, and patient adherence. This mini review outlines current injectable and implantable LADDS, including approved formulations like nanosuspensions, PLGA microspheres, oil-based injections, <em>in situ</em>-forming and preformed implants. Future directions explore thermoresponsive gels, polymer-drug conjugates, prodrugs, 3D printing, and reservoir-type implants using semipermeable membranes. These innovations highlight the need for continued multidisciplinary collaboration to advance next-generation long-acting therapies.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104447"},"PeriodicalIF":7.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797768","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
Ignore at Your Own Risk: American Academic Contributions to the Development of Small Molecule Therapeutics 忽视你自己的风险：美国学术对小分子疗法发展的贡献
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-31 DOI: 10.1016/j.drudis.2025.104438
Michael S. Kinch
{"title":"Ignore at Your Own Risk: American Academic Contributions to the Development of Small Molecule Therapeutics","authors":"Michael S. Kinch","doi":"10.1016/j.drudis.2025.104438","DOIUrl":"10.1016/j.drudis.2025.104438","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104438"},"PeriodicalIF":7.5,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739005","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
Peptide-driven approaches in advanced wound healing materials 肽驱动的方法在先进的伤口愈合材料。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-30 DOI: 10.1016/j.drudis.2025.104440
Chen Zhang , Lei Meng , Gautam Sethi , Jinxiang Wang , Baisen Li
{"title":"Peptide-driven approaches in advanced wound healing materials","authors":"Chen Zhang ,&nbsp;Lei Meng ,&nbsp;Gautam Sethi ,&nbsp;Jinxiang Wang ,&nbsp;Baisen Li","doi":"10.1016/j.drudis.2025.104440","DOIUrl":"10.1016/j.drudis.2025.104440","url":null,"abstract":"<div><div>Peptide-based materials, such as antimicrobial peptides (AMPs), cell-penetrating peptides (CPPs), angiogenic peptides, and extracellular matrix (ECM)-mimetic peptides, offer unique multifunctional benefits for wound healing, including infection control, enhanced angiogenesis, immunomodulation, and tissue regeneration. Representative platforms, including hydrogels, nanofibers, functionalized dressings, and delivery systems, leverage these peptides for sustained therapeutic action and improved healing. Despite these promising advances, significant translational barriers remain, including peptide stability, enzymatic degradation, manufacturing scalability, and regulatory approval. Addressing these barriers through optimized peptide engineering and delivery strategies is essential for the clinical translation and wider clinical adoption of peptide-driven wound therapies.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104440"},"PeriodicalIF":7.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764252","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
Comparative analysis of molecular 3D metrics in fragment space and beyond 分子三维度量在片段空间和其他空间的比较分析。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-29 DOI: 10.1016/j.drudis.2025.104443
Tom Dekker, Maikel Wijtmans, Iwan J.P. de Esch
{"title":"Comparative analysis of molecular 3D metrics in fragment space and beyond","authors":"Tom Dekker,&nbsp;Maikel Wijtmans,&nbsp;Iwan J.P. de Esch","doi":"10.1016/j.drudis.2025.104443","DOIUrl":"10.1016/j.drudis.2025.104443","url":null,"abstract":"<div><div>Within the fragment-based drug discovery (FBDD) community, there is growing interest in developing non-planar, 3D screening fragments to complement the predominantly 2D structures that currently populate fragment libraries. Molecular three-dimensionality is typically evaluated using metrics such as the fraction of sp<sup>3</sup>-hybridized carbon atoms (F<sub>C</sub>sp<sup>3</sup>), plane of best fit (PBF) and/or principal moment of inertia (PMI). In this study, we review these 3D metrics and perform systematic cheminformatic analyses. Furthermore, we explore the use of alternative metrics that consider atom hybridization for the assessment of molecular shape. Although our analysis is grounded in a fragment-based context, the insights gained are broadly applicable across the drug discovery phases.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104443"},"PeriodicalIF":7.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758834","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
Does pharma R&D need a strategic reset? Adapting to a changing US landscape 制药研发需要战略重置吗？适应不断变化的美国环境。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-28 DOI: 10.1016/j.drudis.2025.104442
Sebastian Kwisda , Malte Kremer , Niels Sievertsen , Oliver Gassmann , Dominik Hartl , Alexander Schuhmacher
{"title":"Does pharma R&D need a strategic reset? Adapting to a changing US landscape","authors":"Sebastian Kwisda ,&nbsp;Malte Kremer ,&nbsp;Niels Sievertsen ,&nbsp;Oliver Gassmann ,&nbsp;Dominik Hartl ,&nbsp;Alexander Schuhmacher","doi":"10.1016/j.drudis.2025.104442","DOIUrl":"10.1016/j.drudis.2025.104442","url":null,"abstract":"<div><div>R&amp;D productivity has long challenged research-based pharmaceutical companies, raising concerns about the sustainability of their research-driven business models. These firms have traditionally relied on the U.S. as a stable hub for biomedical innovation, skilled talent, and high-price markets—supporting the biotech-leveraged pharma company (BIPCO) model However, recent geopolitical shifts—especially under the new Trump administration, including FDA budget cuts, reduced U.S. research funding, and pharmaceutical tariffs—are destabilizing this foundation. The once-reliable “safe harbor” is no longer secure. As a result, pharma R&amp;D now faces strategic risks beyond its prior scope. With the weakening of the U.S.-centered innovation model, companies must rethink R&amp;D pipelines, secure key technologies, maintain global clinical networks, and adjust supply chain and tax strategies. The viability of the current R&amp;D model—rooted in U.S. leadership and premium markets—is now uncertain, requiring urgent strategic realignment.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104442"},"PeriodicalIF":7.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751933","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
Transcription factor YBX1 orchestrates drug resistance and tumor progression in HCC 转录因子YBX1调控HCC的耐药和肿瘤进展。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-25 DOI: 10.1016/j.drudis.2025.104439
Dennis Kwabiah , Veerababu Nagati , Manish K. Tripathi
{"title":"Transcription factor YBX1 orchestrates drug resistance and tumor progression in HCC","authors":"Dennis Kwabiah ,&nbsp;Veerababu Nagati ,&nbsp;Manish K. Tripathi","doi":"10.1016/j.drudis.2025.104439","DOIUrl":"10.1016/j.drudis.2025.104439","url":null,"abstract":"<div><div>Drug resistance continues to be a significant challenge in cancer treatment, responsible for over 90% of worldwide cancer-related deaths. Transcription factors (TFs), which control vital cellular processes, also play a crucial role in cancer development and resistance. In hepatocellular carcinoma (HCC), resistance to sorafenib, a primary targeted therapy, significantly impairs treatment effectiveness and worsens patient outcomes. Among TFs, Y-box binding protein 1 (YBX1) has been recognized as a regulator of aggressive cancer traits in colorectal and breast cancers. However, its role in HCC and sorafenib resistance remains unclear. This review examines YBX1’s role in HCC progression and drug resistance, its underlying molecular mechanisms, and its potential as a biomarker and therapeutic target for overcoming sorafenib resistance.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104439"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726262","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
ErbB/HER family in cancer immunology: therapeutic advances and mechanisms 肿瘤免疫学中的ErbB/HER家族：治疗进展和机制。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-24 DOI: 10.1016/j.drudis.2025.104436
Ling Yin , Hongliang Zhang , Yuhua Shang , Songquan Wu , Tengchuan Jin
{"title":"ErbB/HER family in cancer immunology: therapeutic advances and mechanisms","authors":"Ling Yin ,&nbsp;Hongliang Zhang ,&nbsp;Yuhua Shang ,&nbsp;Songquan Wu ,&nbsp;Tengchuan Jin","doi":"10.1016/j.drudis.2025.104436","DOIUrl":"10.1016/j.drudis.2025.104436","url":null,"abstract":"<div><div>The ErbB/HER family has a crucial role in tumor progression and immune responses, offering promising targets for cancer drug discovery. In particular, ErbB/HER-targeted therapeutic agents, in the forms of tyrosine kinase inhibitors (TKIs), monoclonal/bispecific antibodies (mAbs/BsAbs), and antibody–drug conjugates (ADCs), have emerged as effective therapeutic options to achieve excellent clinical outcomes by improving treatment efficacy, reducing drug resistance, and lowering systemic toxicity. Multiple ErbB/HER-targeted therapeutic agents have been used globally for numerous clinical trials, with US Food and Drug Administration (FDA) approval. Furthermore, combination therapy targeting ErbB/HER family members with immunotherapy and chemotherapy enhances therapeutic effects. In this review, we highlight recent advances in single and combined anti-cancer therapeutics targeting ErbB/HER family members, underscoring their potential as transformative treatment strategies. We also discuss recent advances in the structure, mechanism, selectivity, and efficacy of single and combined ErbB/HER-targeted drug design and development efforts, shedding light on their potential to improve cancer treatment.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104436"},"PeriodicalIF":7.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717081","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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