Nature Reviews Drug Discovery最新文献_第2页

Overcoming roadblocks to anti-inflammatory NLRP3 inhibitors. 克服抗炎NLRP3抑制剂的障碍。

Nature Reviews Drug Discovery Pub Date : 2025-09-18 DOI: 10.1038/d41573-025-00156-1

Sarah Crunkhorn

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RNA modification systems as therapeutic targets. RNA修饰系统作为治疗靶点。

Nature Reviews Drug Discovery Pub Date : 2025-09-17 DOI: 10.1038/s41573-025-01280-8

Linda Zhang,Jiangbo Wei,Zhongyu Zou,Chuan He

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Microsystem technologies for accelerating the discovery and translation of immunotherapies 加速免疫疗法发现和转化的微系统技术

Nature Reviews Drug Discovery Pub Date : 2025-09-15 DOI: 10.1038/s41573-025-01268-4

Zongjie Wang, Claire Liu, Kangfu Chen, Joseph Song, Shana O. Kelley

{"title":"Microsystem technologies for accelerating the discovery and translation of immunotherapies","authors":"Zongjie Wang, Claire Liu, Kangfu Chen, Joseph Song, Shana O. Kelley","doi":"10.1038/s41573-025-01268-4","DOIUrl":"https://doi.org/10.1038/s41573-025-01268-4","url":null,"abstract":"Immunotherapies have transformed the treatment of many cancers and autoimmune diseases. However, durable therapeutic benefits are achieved in only certain subsets of patients. Due to the complexity and heterogeneity of disease, it remains challenging to design effective immunotherapies and predict their effects. Microscale systems — including microfluidics, microelectronics and microscaffolds — are now being adapted to accelerate immunotherapy discovery and development, with the potential to address efficacy, toxicity, predictability and affordability challenges. These microsystems consist of miniaturized structures, sensors and actuators that can manipulate molecules and cells of the immune system with high accuracy and throughput. Advances facilitated by microsystem technologies relevant to the discovery and translation of key types of immunotherapy (monoclonal antibodies, cytokine-based drugs, engineered immune cells and therapeutic vaccines) include the development of high-throughput devices for functional selection, miniaturized bioreactors for biomanufacturing, engineered scaffolds for therapeutic administration and sensitive biosensors for immune surveillance post-administration. Challenges facing the clinical translation of microsystem-based immunotherapies include issues related to standardization and integration as well as the need for new regulatory guidance.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthetic lethality in cancer drug discovery: challenges and opportunities 癌症药物发现中的合成致死率：挑战与机遇

Nature Reviews Drug Discovery Pub Date : 2025-09-11 DOI: 10.1038/s41573-025-01273-7

Emanuel Gonçalves, Colm J. Ryan, David J. Adams

{"title":"Synthetic lethality in cancer drug discovery: challenges and opportunities","authors":"Emanuel Gonçalves, Colm J. Ryan, David J. Adams","doi":"10.1038/s41573-025-01273-7","DOIUrl":"https://doi.org/10.1038/s41573-025-01273-7","url":null,"abstract":"Synthetic lethality, first proposed more than two decades ago, has long held immense promise for targeted cancer therapy. Although the clinical success of PARP inhibition in BRCA-mutant cancers stands as proof of concept, few other synthetic lethal interactions have been translated from preclinical findings into effective therapies. This slow pace of translation stems in part from the difficulty of developing drugs against genetic dependencies, but also reflects the cell- and tissue-specific nature of these interactions. In this Review, we outline recent advances in the discovery and validation of synthetic lethal pairs, from their discovery in large-scale genetic screens to the development of drugs for the clinic. We discuss how alternative CRISPR-based approaches — including combinatorial screens, base editing and saturation mutagenesis — are now being used to discover new tractable interactions. We also examine how machine learning models can enable prioritization of candidate pairs and the identification of biomarkers for patient stratification. Finally, we highlight alternative phenotypic readouts, such as high-content imaging and single-cell profiling, which enable the dissection of phenotypes beyond simple cell growth or fitness. Together, these developments are refining the synthetic lethality paradigm and advancing its potential for cancer therapy.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

How multispecific molecules are transforming pharmacotherapy 多特异性分子如何改变药物治疗

Nature Reviews Drug Discovery Pub Date : 2025-08-01 DOI: 10.1038/s41573-025-01262-w

Raymond J. Deshaies

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The non-small-cell lung cancer drug market 非小细胞肺癌药物市场

Nature Reviews Drug Discovery Pub Date : 2025-07-18 DOI: 10.1038/d41573-025-00123-w

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Advances in the treatment of systemic lupus erythematosus 系统性红斑狼疮的治疗进展

Nature Reviews Drug Discovery Pub Date : 2025-07-17 DOI: 10.1038/s41573-025-01242-0

Marc Scherlinger, Antonios G. A. Kolios, Vasileios C. Kyttaris, George C. Tsokos

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CRISPR-based therapeutic genome editing for inherited blood disorders 基于crispr的遗传性血液疾病治疗性基因组编辑

Nature Reviews Drug Discovery Pub Date : 2025-07-14 DOI: 10.1038/s41573-025-01236-y

Sébastien Levesque, Daniel E. Bauer

{"title":"CRISPR-based therapeutic genome editing for inherited blood disorders","authors":"Sébastien Levesque, Daniel E. Bauer","doi":"10.1038/s41573-025-01236-y","DOIUrl":"https://doi.org/10.1038/s41573-025-01236-y","url":null,"abstract":"Therapeutic genome editing promises to transform medicine. Pivotal discoveries have provided a diverse and versatile set of tools to correct pathogenic mutations or produce protective alleles using CRISPR-based technologies. These innovative therapies are especially adaptable for blood and immune disorders, where clinical methods allow haematopoietic stem cells (HSCs) to be mobilized, harvested, engineered ex vivo and transplanted back into a patient to permanently replace their blood system. This paradigm has been exemplified with the first US Food and Drug Administration (FDA)-approved CRISPR–Cas9 therapy for sickle cell disease and β-thalassaemia, exa-cel (Casgevy). Although promising, efficient delivery of gene edits involves complicated ex vivo manipulation and toxic myeloablative conditioning. The quiescent and elusive nature of HSCs also brings associated challenges. In this Review, we explore the state-of-the-art genome editing technologies of nucleases, base editors and prime editors, which hold promise to address unmet clinical needs for patients with inherited haematological disorders. We highlight the progress made for several disorders and discuss the challenges that remain for ex vivo and in vivo targeting of HSCs for next-generation gene therapies.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA chemistry and therapeutics RNA化学和治疗学

Nature Reviews Drug Discovery Pub Date : 2025-07-14 DOI: 10.1038/s41573-025-01237-x

Siyu Wang, Drew Weissman, Yizhou Dong

引用次数: 0

The changing landscape of medicinal chemistry optimization 不断变化的药物化学优化前景

Nature Reviews Drug Discovery Pub Date : 2025-07-07 DOI: 10.1038/s41573-025-01225-1

Anita Rácz, Levente M. Mihalovits, Maximilian Beckers, Nikolas Fechner, Nikolaus Stiefl, Finton Sirockin, William McCoull, Emma Evertsson, Malin Lemurell, Gergely Makara, György M. Keserű

{"title":"The changing landscape of medicinal chemistry optimization","authors":"Anita Rácz, Levente M. Mihalovits, Maximilian Beckers, Nikolas Fechner, Nikolaus Stiefl, Finton Sirockin, William McCoull, Emma Evertsson, Malin Lemurell, Gergely Makara, György M. Keserű","doi":"10.1038/s41573-025-01225-1","DOIUrl":"https://doi.org/10.1038/s41573-025-01225-1","url":null,"abstract":"The goal of a small-molecule drug discovery campaign is the development of chemical entities that fulfil the criteria of the target product profile for progression into clinical trials. This objective is realized through multiparameter medicinal chemistry optimization, typically by identifying the compounds at the hit stage with molecular properties that provide a high chance of subsequent success, and then iteratively optimizing the properties, often in parallel, to identify leads and, ultimately, drug candidates. To assess the impact of medicinal chemistry optimizations on molecular properties, a set of new drug candidates reported in the literature between 2015 and 2022, and their corresponding hit and lead compounds, were analysed, and compared with a set of drug candidates identified between 2000 and 2010, and their corresponding hits and leads. This analysis was complemented by similar analyses of the internal medicinal chemistry programmes pursued at AstraZeneca and Novartis. Here, we highlight and discuss the implications of the observed trends, which include shifts in key physicochemical properties and strategic changes in medicinal chemistry programmes.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0