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IRE1α-mediated UPR activation in gastrointestinal cancers: Adaptive mechanisms and therapeutic potential ire1 α-介导的UPR在胃肠道肿瘤中的激活：适应机制和治疗潜力。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104335
Valappan Veetil Soumya , Baby Jisna , Davis Anu , Chevookaren Francis Binoy , Thekkekara Devassy Babu
{"title":"IRE1α-mediated UPR activation in gastrointestinal cancers: Adaptive mechanisms and therapeutic potential","authors":"Valappan Veetil Soumya ,&nbsp;Baby Jisna ,&nbsp;Davis Anu ,&nbsp;Chevookaren Francis Binoy ,&nbsp;Thekkekara Devassy Babu","doi":"10.1016/j.drudis.2025.104335","DOIUrl":"10.1016/j.drudis.2025.104335","url":null,"abstract":"<div><div>The endoplasmic reticulum (ER) plays a crucial role in protein synthesis, folding and quality control. Disruptions in these processes lead to ER stress (ERS) and activate the unfolded protein response (UPR) to restore cellular homeostasis. In gastrointestinal cancers, inositol-requiring enzyme 1α (IRE1α) is a key regulator of the UPR, enabling cancer cells to adapt to hostile conditions such as hypoxia, oxidative stress and chemotherapy. Elevated IRE1α activity supports tumor survival, progression and metastasis by mitigating ERS-induced apoptosis. However, targeting IRE1α signaling presents a promising therapeutic strategy by impairing cancer cell adaptation to stress, offering promising therapeutic opportunities for gastrointestinal cancers.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 4","pages":"Article 104335"},"PeriodicalIF":6.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646727","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
Covalent inhibitors possessing autophagy-modulating capabilities: charting novel avenues in drug design and discovery 具有自噬调节能力的共价抑制剂：绘制药物设计和发现的新途径。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104347
Yutong Wang , Shiyu Luo , Hongbao Sun , Shuai Huang , Lianhai Shan , Jifa Zhang
{"title":"Covalent inhibitors possessing autophagy-modulating capabilities: charting novel avenues in drug design and discovery","authors":"Yutong Wang ,&nbsp;Shiyu Luo ,&nbsp;Hongbao Sun ,&nbsp;Shuai Huang ,&nbsp;Lianhai Shan ,&nbsp;Jifa Zhang","doi":"10.1016/j.drudis.2025.104347","DOIUrl":"10.1016/j.drudis.2025.104347","url":null,"abstract":"<div><div>Autophagy is a crucial cellular process in degrading damaged organelles and maintaining cellular homeostasis. By forming irreversible bonds with specific proteins, covalent inhibitors present a distinct advantage in regulating autophagy and its related pathways. These inhibitors can provide sustained modulation of autophagy at lower doses, improving therapeutic efficacy while minimizing adverse effects. We discuss their mechanisms, including how they affect autophagy-related enzymes and pathways, and their potential applications in the treatment of cancers and other autophagy-related disorders. Studying autophagy-related pathway targets will provide new insights for the development of covalent inhibitors and enhance therapeutic strategies for complex conditions.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104347"},"PeriodicalIF":6.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778535","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
DCTPP1: A promising target in cancer therapy and prognosis through nucleotide metabolism DCTPP1：通过核苷酸代谢在癌症治疗和预后中有前景的靶点。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104348
Shaoxuan Liu, Li Feng, Zhe Wang
{"title":"DCTPP1: A promising target in cancer therapy and prognosis through nucleotide metabolism","authors":"Shaoxuan Liu,&nbsp;Li Feng,&nbsp;Zhe Wang","doi":"10.1016/j.drudis.2025.104348","DOIUrl":"10.1016/j.drudis.2025.104348","url":null,"abstract":"<div><div>Deoxycytidine triphosphate pyrophosphatase 1 (DCTPP1) is an important deoxycytidine triphosphate (dCTP) hydrolase responsible for eliminating noncanonical dCTP and maintaining deoxyribonucleoside triphosphate (dNTP) pool homeostasis. This regulation is vital for proper DNA replication and genome stability. Emerging evidence highlights the considerable role of DCTPP1 in tumor progression, chemotherapy resistance, and prognostic prediction. Consequently, DCTPP1 has emerged as a promising nucleotide metabolism-related target for cancer therapy. In this review, we provide a comprehensive summary of the structural and cellular biological features of DCTPP1, its functions, and its role in cancer. In addition, we discuss recent advancments in small molecules targeting DCTPP1, and propose potential directions for future research.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104348"},"PeriodicalIF":6.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778537","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
Are leukotrienes really the world’s best bronchoconstrictors and at least 100 to 1000 times more potent than histamine? 白三烯真的是世界上最好的支气管收缩剂，比组胺强至少100到1000倍吗？
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104349
Thomas Boehm, Bernd Jilma
{"title":"Are leukotrienes really the world’s best bronchoconstrictors and at least 100 to 1000 times more potent than histamine?","authors":"Thomas Boehm,&nbsp;Bernd Jilma","doi":"10.1016/j.drudis.2025.104349","DOIUrl":"10.1016/j.drudis.2025.104349","url":null,"abstract":"<div><div>It has been stated numerous times that leukotrienes are 100 to 1000 times more potent compared with histamine, but is this statement correct? Can we really compare a charged mono-cation with lipoid amphiphiles in their ability to penetrate an epithelial cell layer after inhalation challenge? In this review we question the shift in clinical and drug development attention from histamine towards leukotriene receptor antagonists for the treatment of chronic asthma and acute asthma exacerbations. The presented data indicate that histamine very likely plays a much more important role than previously assumed. It is time to rethink mediator involvement during bronchospasm and shift attention back to histamine.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104349"},"PeriodicalIF":6.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778531","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
Drug development for neglected ultra-rare diseases of no commercial interest: Challenges and opportunities 无商业利益的被忽视的超罕见疾病的药物开发：挑战与机遇。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104346
Joseph A. Katakowski , Juan C. López
{"title":"Drug development for neglected ultra-rare diseases of no commercial interest: Challenges and opportunities","authors":"Joseph A. Katakowski ,&nbsp;Juan C. López","doi":"10.1016/j.drudis.2025.104346","DOIUrl":"10.1016/j.drudis.2025.104346","url":null,"abstract":"<div><div>Ultra-rare diseases, particularly those that affect a few hundred patients worldwide, are of little commercial interest to the pharmaceutical industry. Patient-led organizations have made remarkable progress in funding the early-stage, academic development of therapies for such neglected ultra-rare conditions. But the long and difficult path to translate most academic proof-of-concept studies into approved medicines means that very few therapies ever reach patients. Here, we discuss some of the roadblocks to the development of therapeutics for conditions of limited commercial interest and propose ways to overcome these obstacles.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 4","pages":"Article 104346"},"PeriodicalIF":6.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750613","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 modeling approaches and regulatory pathways for drug combinations 药物组合的计算建模方法和调控途径。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-28 DOI: 10.1016/j.drudis.2025.104345
Lucas Fillinger , Samuel Walter , Matthias Ley , Kinga Kęska-Izworska , Leily Ghasemi Dehkordi , Klaus Kratochwill , Paul Perco
{"title":"Computational modeling approaches and regulatory pathways for drug combinations","authors":"Lucas Fillinger ,&nbsp;Samuel Walter ,&nbsp;Matthias Ley ,&nbsp;Kinga Kęska-Izworska ,&nbsp;Leily Ghasemi Dehkordi ,&nbsp;Klaus Kratochwill ,&nbsp;Paul Perco","doi":"10.1016/j.drudis.2025.104345","DOIUrl":"10.1016/j.drudis.2025.104345","url":null,"abstract":"<div><div>Drug combinations offer several advantages over monotherapies, but identifying effective drug combinations while avoiding adverse effects is a major challenge. Computational network models are particularly useful for identifying mechanistically compatible drug combinations and generating hypotheses about their mechanisms of action. Here, we discuss the advantages and challenges of <em>in silico</em> discovery approaches for drug combinations. Obtaining regulatory approval during later stages of product development can be more complex for drug combinations than for single drugs. The regulatory pathway is mainly determined by the approval status of the individual compounds included in a combination. We provide an overview of the regulatory guidelines for drug combination development and discuss trends from previous approvals.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104345"},"PeriodicalIF":6.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750610","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
JAK inhibitors as a promising therapy for immune-mediated photodermatoses JAK抑制剂作为一种有希望的治疗免疫介导的光性皮肤病的方法。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-27 DOI: 10.1016/j.drudis.2025.104344
Mohammad Malekan , Saeid Taghiloo , Armaghan Kazeminejad , Nasim Gholizadeh , Fatemeh Montazer , Ghasem Rahmatpour Rokni
{"title":"JAK inhibitors as a promising therapy for immune-mediated photodermatoses","authors":"Mohammad Malekan ,&nbsp;Saeid Taghiloo ,&nbsp;Armaghan Kazeminejad ,&nbsp;Nasim Gholizadeh ,&nbsp;Fatemeh Montazer ,&nbsp;Ghasem Rahmatpour Rokni","doi":"10.1016/j.drudis.2025.104344","DOIUrl":"10.1016/j.drudis.2025.104344","url":null,"abstract":"<div><div>Immune-mediated photodermatoses (IMPs) are skin diseases caused by altered immune responses triggered by sunlight, including polymorphous light eruption (PMLE), actinic prurigo (AP), solar urticaria (SU), chronic actinic dermatitis (CAD), and hydroa vacciniforme (HV). Managing IMPs is challenging because of the need for rigorous sun protection and the poor response to conventional therapies, particularly in moderate-to-severe patients. Researchers are exploring new targeted therapies for IMPs, including Janus kinase (JAK) inhibitors, a novel class of small molecules that block the JAK–STAT signaling pathway. Several case reports and series show promising results. This study reviews the evidence-based rationale for using JAK inhibitors in IMP treatment, assessing their efficacy and safety.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104344"},"PeriodicalIF":6.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741962","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
Drug–device combinations in rare diseases: Challenges and opportunities 罕见病的药物器械组合：挑战与机遇。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-22 DOI: 10.1016/j.drudis.2025.104343
E.A. Tataru , M. Dooms , C. Gonzaga-Jauregui , A.M.G. Pasmooij , D.J. O’Connor , A.H. Jonker
{"title":"Drug–device combinations in rare diseases: Challenges and opportunities","authors":"E.A. Tataru ,&nbsp;M. Dooms ,&nbsp;C. Gonzaga-Jauregui ,&nbsp;A.M.G. Pasmooij ,&nbsp;D.J. O’Connor ,&nbsp;A.H. Jonker","doi":"10.1016/j.drudis.2025.104343","DOIUrl":"10.1016/j.drudis.2025.104343","url":null,"abstract":"<div><div>Drug–device combinations (DDCs) are therapeutic products that integrate drugs with medical devices to enhance treatment efficacy and/or safety. These combinations hold significant promise for rare diseases, which affect millions of patients globally, by improving drug delivery, targeting specific organs, and reducing side effects. However, the regulatory framework for DDCs remains complex and lacks specific incentives for rare diseases, unlike orphan drugs. This review examines regulatory approaches and case studies of DDCs in rare diseases, and highlights specific challenges and untapped opportunities. Moreover, the publication discusses recommendations to overcome these challenges through tailored policies and incentives to unlock the potential of DDCs in the context of rare diseases.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 4","pages":"Article 104343"},"PeriodicalIF":6.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690620","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
Gastroretentive drug delivery systems: A holy grail in oral delivery 胃保留性给药系统：口服给药的圣杯。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-21 DOI: 10.1016/j.drudis.2025.104340
Hossein Omidian
{"title":"Gastroretentive drug delivery systems: A holy grail in oral delivery","authors":"Hossein Omidian","doi":"10.1016/j.drudis.2025.104340","DOIUrl":"10.1016/j.drudis.2025.104340","url":null,"abstract":"<div><div>Gastroretentive drug delivery systems (GRDDSs) offer a promising strategy for enhancing oral drug bioavailability by prolonging gastric residence time and enabling site-specific drug release. This review examines the key materials used in GRDDSs, including polymers for controlled drug release, gas-generating agents for buoyancy, and mucoadhesive components for improved retention and stability. Advances in fabrication techniques, such as 3D printing, spray drying, and nanoparticle encapsulation, have enabled precise modulation of drug release kinetics and retention properties. However, challenges such as inter-subject variability, physiological constraints, and manufacturing scalability remain. Future research will focus on smart materials, multi-drug platforms, and expanding applications to biologics and nutraceuticals, paving the way for more effective and patient-compliant oral drug delivery systems.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 4","pages":"Article 104340"},"PeriodicalIF":6.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690625","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-term follow-up after authorization of gene therapy: leveraging real-world data 基因治疗授权后的长期随访：利用真实世界数据。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-03-19 DOI: 10.1016/j.drudis.2025.104337
Karin de Haart , Keiko Asao , Quazi Ataher , Jamie Geier , Jodie Hillen , Kui Huang , Peter G.M. Mol , Donna Rivera , Huifen Wang , Hong Yang , Siyan Zhan , Wilhelmina E. Hoogendoorn , Lourens T. Bloem
{"title":"Long-term follow-up after authorization of gene therapy: leveraging real-world data","authors":"Karin de Haart ,&nbsp;Keiko Asao ,&nbsp;Quazi Ataher ,&nbsp;Jamie Geier ,&nbsp;Jodie Hillen ,&nbsp;Kui Huang ,&nbsp;Peter G.M. Mol ,&nbsp;Donna Rivera ,&nbsp;Huifen Wang ,&nbsp;Hong Yang ,&nbsp;Siyan Zhan ,&nbsp;Wilhelmina E. Hoogendoorn ,&nbsp;Lourens T. Bloem","doi":"10.1016/j.drudis.2025.104337","DOIUrl":"10.1016/j.drudis.2025.104337","url":null,"abstract":"<div><div>Gene therapies are innovative treatments that could revolutionize healthcare. Given their unique mechanisms of action, methods of manufacturing and administration, and the potential for long-lasting impact, gene therapies require long-term follow-up (LTFU) of safety and effectiveness post-authorization, often using real-world data (RWD). With over 2000 gene therapies in development, there is a need for knowledge-building regarding LTFU studies. Here, we review regulatory, scientific, and operational requirements and considerations for LTFU studies using RWD from a global perspective. The insights in this review support post-authorization LTFU studies for gene therapies, thereby contributing to their safe and effective use.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104337"},"PeriodicalIF":6.5,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673103","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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