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The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery 纺锤体组装检查点：分子机制和激酶靶向药物的发现
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-10 DOI: 10.1016/j.drudis.2025.104355
Inês Lima , Fernanda Borges , António Pombinho , Daniel Chavarria
{"title":"The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery","authors":"Inês Lima ,&nbsp;Fernanda Borges ,&nbsp;António Pombinho ,&nbsp;Daniel Chavarria","doi":"10.1016/j.drudis.2025.104355","DOIUrl":"10.1016/j.drudis.2025.104355","url":null,"abstract":"<div><div>The spindle assembly checkpoint (SAC) is a surveillance mechanism required for the fidelity of chromosome segregation, ensuring that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. In cancer cells, SAC inactivation leads to aneuploidy beyond the cell’s adaptation, culminating in cell death. This review provides a concise overview of the SAC signaling process and properties. Recent drug discovery strategies to selectively target kinases, particularly Aurora B and monopolar spindle kinase (MPS1), aimed at developing innovative anticancer agents able to override SAC are also presented.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104355"},"PeriodicalIF":6.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847966","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
Selective imaging probes for differential detection of pathological tau polymorphs in tauopathies 选择性成像探针在tau病变中病理tau多态性的鉴别检测
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-10 DOI: 10.1016/j.drudis.2025.104352
Nicolò Bisi, Luca Pinzi, Giulio Rastelli
{"title":"Selective imaging probes for differential detection of pathological tau polymorphs in tauopathies","authors":"Nicolò Bisi,&nbsp;Luca Pinzi,&nbsp;Giulio Rastelli","doi":"10.1016/j.drudis.2025.104352","DOIUrl":"10.1016/j.drudis.2025.104352","url":null,"abstract":"<div><div>Tauopathies, including Alzheimer’s disease (AD), Pick’s disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are characterized by the misfolding and pathological aggregation of the tau protein, leading to neurodegeneration. Although the pathogenesis of these diseases is still a matter for debate, the formation of amyloid inclusions still represents the only histopathological hallmark available. Tau inclusions are not the same in terms of structure and morphology, and different tauopathies are characterized by different polymorphs. Remarkably, the selective detection of these polymorphs is crucial for differential diagnosis, disease monitoring and evaluation of the potential harmfulness of polymorphs, with a significant impact on drug discovery. This review discusses recent advances in the development of imaging probes designed for the selective detection of pathological tau forms associated with specific tauopathies. We explore the application of compounds that can target tau polymorphs characteristic of AD, PiD, PSP and CBD. In particular, we focus on discussing the probes’ selectivity and sensitivity in distinguishing between the different tauopathy-associated polymorphs in preclinical settings. The progress and the weaknesses in this field are discussed, to guide the researchers in identifying accurate and potent probes for the selective diagnosis of these different neurodegenerative diseases.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104352"},"PeriodicalIF":6.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847979","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
Therapeutic potential of targeting ubiquitin-specific proteases in colorectal cancer 靶向泛素特异性蛋白酶在结直肠癌中的治疗潜力
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-10 DOI: 10.1016/j.drudis.2025.104356
Chern Ein Oon , Padmanabhan Anbazhagan , Chong Teik Tan
{"title":"Therapeutic potential of targeting ubiquitin-specific proteases in colorectal cancer","authors":"Chern Ein Oon ,&nbsp;Padmanabhan Anbazhagan ,&nbsp;Chong Teik Tan","doi":"10.1016/j.drudis.2025.104356","DOIUrl":"10.1016/j.drudis.2025.104356","url":null,"abstract":"<div><div>Ubiquitin-specific proteases (USPs) are a subset of deubiquitinating enzymes (DUBs) that have crucial roles in regulating key signaling pathways, DNA repair mechanisms, and immune responses by modulating the interactions and stability of proteins, including oncogenes and tumor suppressors in many cancers, such as colorectal cancer (CRC). USPs present an attractive reservoir of drug targets that could potentially overcome the shortcomings of conventional pathway-specific cancer therapies. This review explores the roles of USPs in CRC, addresses the challenges in discovering and developing USP inhibitors, highlights recent advancements in drug development, and discusses the potential of targeted protein degraders and stabilizers including proteolysis-targeting chimeras (PROTACs), molecular glues, and DUB-targeting chimeras (DUBTACs) as strategies for drugging USPs.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104356"},"PeriodicalIF":6.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864478","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
Every Compound a Candidate: experience-led risk-taking approaches to accelerate small-molecule drug discovery 每一种化合物都是候选物：以经验为导向的冒险方法加速小分子药物的发现
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-08 DOI: 10.1016/j.drudis.2025.104354
Dermot F. McGinnity , Jerome Meneyrol , Christophe Boldron , Craig Johnstone
{"title":"Every Compound a Candidate: experience-led risk-taking approaches to accelerate small-molecule drug discovery","authors":"Dermot F. McGinnity ,&nbsp;Jerome Meneyrol ,&nbsp;Christophe Boldron ,&nbsp;Craig Johnstone","doi":"10.1016/j.drudis.2025.104354","DOIUrl":"10.1016/j.drudis.2025.104354","url":null,"abstract":"<div><div>Despite progress, small-molecule drug discovery remains slow and costly. A paradigm shift is underway by leveraging artificial intelligence (AI) and machine learning (ML); however, these technological advances are necessary but not sufficient. Performance indicators from our partnered portfolio include timelines for data turnaround (5-day) and candidate delivery (2.9 versus 4.0 years for industry). Together with optimised processes and effective decision-making, improved translational predictivity is required. Progressing more compounds through downstream <em>in vitro</em> and <em>in vivo</em> models will rapidly reveal translational thresholds or crucial blockers for compound progression, with humans and machines actively learning from such data. We advocate for more experience-led risk-taking and a mindset shift toward an Every Compound a Candidate strategy, which aims to deliver drug candidates in &lt;2 years.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104354"},"PeriodicalIF":6.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843047","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
Pathogenic TDP-43 in amyotrophic lateral sclerosis 肌萎缩性侧索硬化致病性TDP-43。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-04 DOI: 10.1016/j.drudis.2025.104351
Zhao Zhong Chong, Nizar Souayah
{"title":"Pathogenic TDP-43 in amyotrophic lateral sclerosis","authors":"Zhao Zhong Chong,&nbsp;Nizar Souayah","doi":"10.1016/j.drudis.2025.104351","DOIUrl":"10.1016/j.drudis.2025.104351","url":null,"abstract":"<div><div>The aberrant expression of the transactive response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the <em>TARDBP</em> gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104351"},"PeriodicalIF":6.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794408","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 connection between Bayesian networks and adverse outcome pathway (AOP) networks and how to use it for predicting drug toxicity 研究了贝叶斯网络与不良结果通路（adverse outcome pathway， AOP）网络的联系及其在药物毒性预测中的应用。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-03 DOI: 10.1016/j.drudis.2025.104350
Dong Wang , Ayako Suzuki , Weida Tong
{"title":"The connection between Bayesian networks and adverse outcome pathway (AOP) networks and how to use it for predicting drug toxicity","authors":"Dong Wang ,&nbsp;Ayako Suzuki ,&nbsp;Weida Tong","doi":"10.1016/j.drudis.2025.104350","DOIUrl":"10.1016/j.drudis.2025.104350","url":null,"abstract":"<div><div>There is significant interest in combining adverse outcome pathways (AOPs) with Bayesian networks (BNs) because of their shared representation using directed acyclic graphs (DAGs). However, it has not been verified empirically whether AOP networks are mathematically congruent with BNs. Furthermore, important properties for BNs, such as Markov blankets, have not been emphasized, which is a missed opportunity for simplifying and optimizing the model. Here, we summarize the connection between AOP networks and BNs and explore the implications for toxicity modeling. We also present a case study in drug-related liver toxicity. Our results confirm that AOP networks are congruent mathematically with BNs, with incorporation of the mathematical properties of BN leading to significantly simplified and more efficient models.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 5","pages":"Article 104350"},"PeriodicalIF":6.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787454","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
Overview of new indications for novel drugs approved in China between 2018 and 2024 2018 - 2024年中国获批新药新适应症综述
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104342
Yang Xu , Qixiang Guo , Ziqi Chen , Yunpeng Liu , Yue Yang
{"title":"Overview of new indications for novel drugs approved in China between 2018 and 2024","authors":"Yang Xu ,&nbsp;Qixiang Guo ,&nbsp;Ziqi Chen ,&nbsp;Yunpeng Liu ,&nbsp;Yue Yang","doi":"10.1016/j.drudis.2025.104342","DOIUrl":"10.1016/j.drudis.2025.104342","url":null,"abstract":"<div><div>Since China’s regulatory reforms were initiated in 2015, the development of new indications for novel drugs has become an important trend. Between 2018 and 2024, China’s National Medical Products Administration (NMPA) approved 313 new indications for 151 novel drugs. This cross-sectional study comprehensively depicts the landscape of China’s new indications for novel drugs, including the characteristics of approvals, quality, and quantity of clinical trial evidence. The quality characteristics of the efficacy evidence for new indications were affected by the treatment areas and conditional approval programs. The efficacy of a novel drug for a new indication can be demonstrated by one pivotal trial or one pivotal trial plus supportive evidence in most cases.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 4","pages":"Article 104342"},"PeriodicalIF":6.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690629","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 Six Ds of Exponentials and drug discovery: A path toward reversing Eroom’s law 指数的六个d和药物发现：一条逆转厄鲁姆定律的道路。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104341
Alexander Tropsha , Holli-Joi Martin , Artem Cherkasov
{"title":"The Six Ds of Exponentials and drug discovery: A path toward reversing Eroom’s law","authors":"Alexander Tropsha ,&nbsp;Holli-Joi Martin ,&nbsp;Artem Cherkasov","doi":"10.1016/j.drudis.2025.104341","DOIUrl":"10.1016/j.drudis.2025.104341","url":null,"abstract":"<div><div>Many technological sectors underwent recent exponential growth because of digital disruption, a phenomenon Peter Diamantis characterized as the ‘Six Ds of Exponentials’: digitization, deception, disruption, demonetization, dematerialization, and democratization. In contrast, drug discovery has been marked by rising costs and modest growth, if any, of annual drug approvals. We argue that the exponential growth of drug discovery can be also achieved through digital disruption brought by data expansion, mature artificial intelligence (AI), automation of experiments, public–private partnerships, and open science. We detected the emergence of all ‘Six Ds of Exponentials’ within modern drug discovery and discuss how each of the ‘Six Ds’ can further empower the field and forcefully address the societal demand for novel, potent, affordable, and accessible medicines.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 4","pages":"Article 104341"},"PeriodicalIF":6.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690632","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
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
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