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PK/PD modeling of targeted protein degraders: Charting new waters and navigating the shallows
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-01 DOI: 10.1016/j.drudis.2025.104311
Robin T.U. Haid , Andreas Reichel
{"title":"PK/PD modeling of targeted protein degraders: Charting new waters and navigating the shallows","authors":"Robin T.U. Haid ,&nbsp;Andreas Reichel","doi":"10.1016/j.drudis.2025.104311","DOIUrl":"10.1016/j.drudis.2025.104311","url":null,"abstract":"<div><div>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, this 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.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104311"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389760","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
Computational insights into fucoidan–receptor binding: Implications for fucoidan-based targeted drug delivery 褐藻糖胶与受体结合的计算见解：对基于褐藻糖胶的靶向给药的影响。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-01 DOI: 10.1016/j.drudis.2025.104315
Rumana Ferdushi , Dohyeon Kim , Dinesh Kumar Sriramulu , Yoonho Hwang , Keunwan Park , Jaehong Key
{"title":"Computational insights into fucoidan–receptor binding: Implications for fucoidan-based targeted drug delivery","authors":"Rumana Ferdushi ,&nbsp;Dohyeon Kim ,&nbsp;Dinesh Kumar Sriramulu ,&nbsp;Yoonho Hwang ,&nbsp;Keunwan Park ,&nbsp;Jaehong Key","doi":"10.1016/j.drudis.2025.104315","DOIUrl":"10.1016/j.drudis.2025.104315","url":null,"abstract":"<div><div>Fucoidan, a polysaccharide from seaweed, holds promise as a drug delivery system and immune modulator; however, its exact mechanism of action remains unclear. As various carbohydrates play key roles in immune responses by binding to carbohydrate-binding proteins like lectins, fucoidan is hypothesized to interact with immune receptors, potentially driving its anticancer activities. However, structural variability, extraction-induced heterogeneity, and weak binding affinities pose challenges to research. Computational tools offer valuable insights into fucoidan–receptor interactions, addressing these challenges and enabling the design of more effective therapies. This review examines fucoidan’s therapeutic activities, drug delivery potential, and receptor interactions, emphasizing computational approaches to advance immune modulation and anticancer applications using carbohydrate polymers.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104315"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472011","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 feasibility of using real world data as external control arms in oncology trials
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-01 DOI: 10.1016/j.drudis.2025.104324
Lishi Lin , Merel J.J. Lucassen , Vincent van der Noort , Toine C.G. Egberts , Jos H. Beijnen , Alwin D.R. Huitema
{"title":"The feasibility of using real world data as external control arms in oncology trials","authors":"Lishi Lin ,&nbsp;Merel J.J. Lucassen ,&nbsp;Vincent van der Noort ,&nbsp;Toine C.G. Egberts ,&nbsp;Jos H. Beijnen ,&nbsp;Alwin D.R. Huitema","doi":"10.1016/j.drudis.2025.104324","DOIUrl":"10.1016/j.drudis.2025.104324","url":null,"abstract":"<div><div>Before real world data (RWD)-derived external control arms (ECAs) can be applied in clinical trials within the field of oncology, it must be determined whether these ECAs can function as appropriate and reliable control arms. This review provides an overview of studies in which RWD-derived ECAs were constructed and compared to a randomized clinical trial (RCT) arm. RWD-derived ECAs had similar survival outcomes as the RCT arm of comparison in six of the eight included studies. Therefore, when performing RCTs is not feasible, RWD-derived ECAs can act as control arms in single-arm clinical trials, provided that suitable RWD sources are used and suitable methodological decisions are made.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104324"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584052","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
Transforming brain cancer biomarker research with patinformatics and SWOT analysis
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-01 DOI: 10.1016/j.drudis.2025.104314
Neha Saini , Amit Kumar Tiwari , Robert Leahy , Nanasaheb Thorat , Atul Kulkarni
{"title":"Transforming brain cancer biomarker research with patinformatics and SWOT analysis","authors":"Neha Saini ,&nbsp;Amit Kumar Tiwari ,&nbsp;Robert Leahy ,&nbsp;Nanasaheb Thorat ,&nbsp;Atul Kulkarni","doi":"10.1016/j.drudis.2025.104314","DOIUrl":"10.1016/j.drudis.2025.104314","url":null,"abstract":"<div><div>Brain cancer heterogeneity imposes significant challenges in diagnosis, causing high mortality. The lack of timely diagnosis intensifies these challenges, underscoring the need for improved diagnostics. Recent advancements in biomarker discovery have led to biomarker detection at ultra-low concentrations via multiplexing with biosensors, offering a promising avenue for the timely detection of brain cancer. Serving as a comprehensive resource, this review highlights the crucial role of primary biomarkers in brain cancer diagnosis via integration of patinformatics and SWOT analysis, thereby facilitating timely diagnosis and informed decision making. Furthermore, we aim to outline recent advances in brain cancer prognostics and management strategies, ultimately improving patient outcomes.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104314"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456555","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
Effects of PCSK9 inhibitors on cancer, diabetes, and cardiovascular diseases
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-01 DOI: 10.1016/j.drudis.2025.104316
Mojgan Nejabat , Farzin Hadizadeh , Wael Almahmeed , Amirhossein Sahebkar
{"title":"Effects of PCSK9 inhibitors on cancer, diabetes, and cardiovascular diseases","authors":"Mojgan Nejabat ,&nbsp;Farzin Hadizadeh ,&nbsp;Wael Almahmeed ,&nbsp;Amirhossein Sahebkar","doi":"10.1016/j.drudis.2025.104316","DOIUrl":"10.1016/j.drudis.2025.104316","url":null,"abstract":"<div><div>Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have potential applications in cancer therapy and as cholesterol-lowering treatments. The impact of PCSK9 suppression on both tumor growth and metastasis, as well as the management of diabetes, has been demonstrated. PCSK9i can also enhance outcomes and reduce cardiovascular (CV) events in individuals with a history of such events. In this review, we provide insights into the pharmacology, safety, and impact of PCSK9i. We highlight cutting-edge investigations, the development of innovative PCSK9i-based products, and a more comprehensive understanding of the potential effects of these drugs on cancer, diabetes, and CV and cerebrovascular diseases.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104316"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475908","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
Polysaccharides as therapeutic vehicles in pancreatic cancer
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-01 DOI: 10.1016/j.drudis.2025.104320
Seema Kumari , Sujatha Peela , Ganji Purnachandra Nagaraju , Mundla Srilatha
{"title":"Polysaccharides as therapeutic vehicles in pancreatic cancer","authors":"Seema Kumari ,&nbsp;Sujatha Peela ,&nbsp;Ganji Purnachandra Nagaraju ,&nbsp;Mundla Srilatha","doi":"10.1016/j.drudis.2025.104320","DOIUrl":"10.1016/j.drudis.2025.104320","url":null,"abstract":"<div><div>Pancreatic cancer (PC) is highly aggressive, with rising incidence and mortality rates. It has significant therapy obstacles due to the limited clinical options, late-stage identification, dense tumor microenvironment (TME), and resistance to therapy. Recent advances might improve treatment consequences in therapy strategies that target important TME components. Moreover, new polymeric drug delivery techniques based on polysaccharides such as polymeric micelles, liposomes, and nanoparticles enhance the solubility of drugs, drug stability, and tumor-specific targeting, which increase the chances of circumventing resistance and improving the efficacy of treatment. Preclinical research has suggested that by modulating the TME and enhancing the efficacy of chemotherapy, polysaccharide-based therapy, such as RP02-1 and DPLL-functionalized amylose, may help treat PC.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104320"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536290","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
Recent advancements in colchicine derivatives: Exploring synthesis, activities, and nanoformulations for enhanced therapeutic efficacy
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-11 DOI: 10.1016/j.drudis.2025.104312
Marialucia Rubicondo , Gianluca Ciardelli , Clara Mattu , Jack A. Tuszynski
{"title":"Recent advancements in colchicine derivatives: Exploring synthesis, activities, and nanoformulations for enhanced therapeutic efficacy","authors":"Marialucia Rubicondo ,&nbsp;Gianluca Ciardelli ,&nbsp;Clara Mattu ,&nbsp;Jack A. Tuszynski","doi":"10.1016/j.drudis.2025.104312","DOIUrl":"10.1016/j.drudis.2025.104312","url":null,"abstract":"<div><div>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 <em>in vitro</em> 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.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 3","pages":"Article 104312"},"PeriodicalIF":6.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412562","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
Pharma fusion? Don’t buy your alliances partners if the goal is breakthrough innovation
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-02-06 DOI: 10.1016/j.drudis.2025.104310
Killian McCarthy , Rick Aalbers
{"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
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
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