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Recent advancements in colchicine derivatives: Exploring synthesis, activities, and nanoformulations for enhanced therapeutic efficacy.
IF 6.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-11 DOI: 10.1016/j.drudis.2025.104312
Marialucia Rubicondo, Gianluca Ciardelli, Clara Mattu, Jack A Tuszynski

The multifaceted anti-cancer properties of colchicine make it a promising candidate for tumor treatment. However, its application has been limited by poor solubility, low bioavailability, and systemic toxicity. Considerable efforts have been directed toward the development of colchicine derivatives and nanoformulations to overcome these challenges. In this review, we provide a comprehensive overview of recent advances in colchicine derivatives and nanoformulations for cancer treatment. Synthesis methods and in vitro antiproliferative assays for the reviewed derivatives and formulations are explored. Challenges, such as drug resistance and formulation optimization, are also addressed, along with future perspectives for leveraging the full potential of colchicine derivatives and their nanoformulations as innovative anti-cancer strategies, toward successful clinical applications.

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引用次数: 0
PK/PD modeling of targeted protein degraders: Charting new waters and navigating the shallows.
IF 6.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-08 DOI: 10.1016/j.drudis.2025.104311
Robin T U Haid, Andreas Reichel

The development of targeted protein degraders has picked up considerable steam recently, with interest stoked further by the first compounds entering Phase III studies. To keep up with leading biotech start-up firms, big pharma has been keen to venture into this new field, bringing along experienced crews of drug hunters. At their disposal, they find a burgeoning body of literature on pharmacokinetics/pharmacodynamics (PK/PD) models tailor‑made for this new therapeutic modality. However, the ocean of opportunities might seem daunting even to veteran scientists. Here, we provide orientation and direction for researchers to find the approach best suited for their respective questions.

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引用次数: 0
Pharma fusion? Don’t buy your alliances partners if the goal is breakthrough innovation
IF 6.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-06 DOI: 10.1016/j.drudis.2025.104310
Killian McCarthy , Rick Aalbers
This paper examines the innovation impact of acquiring alliance partners. We argue that although pre-acquisition alliances might aid post-acquisition integration efforts, by offering insights into targets’ proprietary technologies, the familiarity that they foster will also significantly influence the firms post-acquisition innovation outcomes. We tested this using a dataset involving 252 firms, 2398 acquisitions, and 125,440 patents. We found that acquisitions involving former alliance partners increased innovation output. We also found that they fostered the development of more exploitative innovation. However, we found that these transitions inhibit the development of breakthrough innovation by limiting the firm’s exposure to novel insights. We conclude, therefore, that alliance partner acquisitions are far from an innovation panacea for the pharm industry.
{"title":"Pharma fusion? Don’t buy your alliances partners if the goal is breakthrough innovation","authors":"Killian McCarthy ,&nbsp;Rick Aalbers","doi":"10.1016/j.drudis.2025.104310","DOIUrl":"10.1016/j.drudis.2025.104310","url":null,"abstract":"<div><div>This paper examines the innovation impact of acquiring alliance partners. We argue that although pre-acquisition alliances might aid post-acquisition integration efforts, by offering insights into targets’ proprietary technologies, the familiarity that they foster will also significantly influence the firms post-acquisition innovation outcomes. We tested this using a dataset involving 252 firms, 2398 acquisitions, and 125,440 patents. We found that acquisitions involving former alliance partners increased innovation output. We also found that they fostered the development of more exploitative innovation. However, we found that these transitions inhibit the development of breakthrough innovation by limiting the firm’s exposure to novel insights. We conclude, therefore, that alliance partner acquisitions are far from an innovation panacea for the pharm industry.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104310"},"PeriodicalIF":6.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373501","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
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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104299
Khalid Rashid , Holger Kalthoff , Sarki A. Abdulkadir , Dieter Adam
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.
{"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 Q1 PHARMACOLOGY & PHARMACY 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
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.
{"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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104290
Lu Zhang , Yueying Yang , Jianjun Tan
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.
目前的治疗药物不足以治愈肿瘤,这凸显了对新型肿瘤药物的需求。单细胞RNA测序(scRNA-seq)技术的进步为肿瘤药物的发现提供了新的机遇。这项技术使我们能够在单细胞水平上探索肿瘤的异质性和发育机制。在本文中,我们概述了scRNA-seq在肿瘤药物发现阶段的应用,包括阐明肿瘤机制、确定靶点、筛选药物、了解药物作用和耐药性。我们还讨论了在药物开发中使用scRNA-seq的挑战和未来前景,为推进肿瘤治疗提供科学基础。
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引用次数: 0
Artificial intelligence in peptide-based drug design
IF 6.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY 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
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.
{"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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104298
Marc Reichel , Eva M. Murauer , Martin Steiner , Christoph Coch , Hubert Trübel
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.
{"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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104306
Alexander Schuhmacher , Kyrylo Grinchenko , Oliver Gassmann , Dominik Hartl , Markus Hinder
Despite a recent increase in FDA new drug approvals, leading pharmaceutical companies continue to face R&D productivity challenges. This highlights the need to better understand the context of their R&D concepts and related R&D outputs. Consequently, we conducted a systematic assessment of the impact of R&D expenditures, R&D intensities, mergers & acquisitions (M&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&D factors: whereas R&D expenditures and the number of M&A deals correlate with the number of new drug approvals, our analysis shows no correlation with R&D intensity or the number of licensing agreements.
{"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
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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.drudis.2025.104295
Pedro Franco , Stefan Haefliger
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.
商业生态系统之间的竞争不仅与战略管理有关,而且与卫生政策和监管机构有关。监管是生态系统竞争的一个关键因素,政府和监管机构实施新的制药立法、政策和指导方针,有助于创造能够吸引初创企业、生物技术公司和制药行业投资创新药物和技术的商业环境。对患者和社会福利的影响需要对旨在增强欧洲联盟(EU)在吸引制药公司优先提交其创新药物方面的竞争优势的战略进行彻底分析。这种分析对于确保患者及时获得新的治疗方法、社会从医疗保健的进步中受益以及促进欧洲监管生态系统的竞争优势至关重要。在这里,我们提供了来自65位制药行业专业人士的访谈数据,为监管生态系统竞争和全球卫生政策提供了直接见解。我们的报告强调了制定有效战略以增强欧洲监管体系竞争优势的必要性。
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引用次数: 0
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Drug Discovery Today
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