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At last: the mitochondrial pyruvate carrier structure revealed! 最终：线粒体丙酮酸载体结构揭示！
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-10 DOI: 10.1016/j.tips.2025.05.010
Brian N Finck, Christy M Hadfield, Kyle S McCommis
{"title":"At last: the mitochondrial pyruvate carrier structure revealed!","authors":"Brian N Finck, Christy M Hadfield, Kyle S McCommis","doi":"10.1016/j.tips.2025.05.010","DOIUrl":"10.1016/j.tips.2025.05.010","url":null,"abstract":"<p><p>Mitochondrial pyruvate carrier (MPC) inhibitors have shown promise as therapeutics for treating several chronic diseases. However, the structure of MPC and the molecular mechanisms by which it interacts with inhibitors have remained unclear, impeding rational drug design. Multiple groups have now independently resolved the structure of the MPC heterodimer.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"596-598"},"PeriodicalIF":19.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Givinostat: a histone deacetylase inhibitor for Duchenne muscular dystrophy. 吉维司他：一种治疗杜氏肌营养不良的组蛋白去乙酰化酶抑制剂。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-05-15 DOI: 10.1016/j.tips.2025.04.006
Melis Sucuoglu, Serkan Kir
{"title":"Givinostat: a histone deacetylase inhibitor for Duchenne muscular dystrophy.","authors":"Melis Sucuoglu, Serkan Kir","doi":"10.1016/j.tips.2025.04.006","DOIUrl":"10.1016/j.tips.2025.04.006","url":null,"abstract":"","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"692-693"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Mining microbial metabolites of GPCR-targeted drugs. 挖掘gpcr靶向药物的微生物代谢物。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-18 DOI: 10.1016/j.tips.2025.05.014
Chen Zhang, Peter J Turnbaugh
{"title":"Mining microbial metabolites of GPCR-targeted drugs.","authors":"Chen Zhang, Peter J Turnbaugh","doi":"10.1016/j.tips.2025.05.014","DOIUrl":"10.1016/j.tips.2025.05.014","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are a large superfamily of receptors critical for mammalian cell-cell communication and a common drug target. A new study has revealed that the human gut microbiome can metabolize GPCR-targeted drugs into both expected and surprising metabolites, with potentially broad implications for the treatment of disease.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"590-592"},"PeriodicalIF":19.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Anti-remodeling therapies in pulmonary arterial hypertension. 肺动脉高压的抗重塑治疗。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-19 DOI: 10.1016/j.tips.2025.05.004
Olivier Boucherat, Sébastien Bonnet, Steeve Provencher, François Potus
{"title":"Anti-remodeling therapies in pulmonary arterial hypertension.","authors":"Olivier Boucherat, Sébastien Bonnet, Steeve Provencher, François Potus","doi":"10.1016/j.tips.2025.05.004","DOIUrl":"10.1016/j.tips.2025.05.004","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive, life-threatening vasculopathy characterized by sustained vasoconstriction and pathological remodeling of small pulmonary arteries. While current vasodilator therapies improve symptoms and survival, they are not curative and fail to reverse vascular remodeling. Recently, a shift toward disease-modifying strategies has emerged, driven by preclinical advances now entering clinical translation. The approval of sotatercept, the first agent presumed to target vascular remodeling, and the development of seralutinib, an inhaled tyrosine kinase inhibitor (TKI), mark key milestones. In this review, we focus on anti-remodeling therapies that have progressed from preclinical models to clinical trials. These include agents targeting cell cycle regulators, kinase pathways, epigenetic modifiers, bone morphogenetic protein receptor type 2 (BMPR2) signaling, and senescence in pulmonary arterial smooth muscle cells (PASMCs), offering renewed hope for durable PAH treatment.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"674-691"},"PeriodicalIF":19.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
GPR17 - orphan G protein-coupled receptor with therapeutic potential. GPR17 -孤儿G蛋白偶联受体，具有治疗潜力。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-20 DOI: 10.1016/j.tips.2025.05.001
Michael Lewash, Evi Kostenis, Christa E Müller
{"title":"GPR17 - orphan G protein-coupled receptor with therapeutic potential.","authors":"Michael Lewash, Evi Kostenis, Christa E Müller","doi":"10.1016/j.tips.2025.05.001","DOIUrl":"10.1016/j.tips.2025.05.001","url":null,"abstract":"<p><p>The orphan G protein-coupled receptor (GPCR) GPR17, whose physiological agonist remains unknown, has emerged as a promising drug target for multiple sclerosis (MS). Blockade of the receptor enables remyelination and may offer a novel therapeutic strategy for MS. Only recently, potent and selective tool compounds for GPR17 have become available, and patents on antagonists have surged, leading to the first clinical candidate, the GPR17 antagonist PTD802, which is to be developed for MS therapy. This may pave the way for further clinical studies exploring additional indications, such as neurodegenerative diseases. The newly determined cryo-electron microscopy (cryo-EM) structure of GPR17 is expected to facilitate future structure-based drug design efforts. This review presents and discusses these latest developments, providing a timely and comprehensive overview to guide future research in the field.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"610-628"},"PeriodicalIF":19.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Exploring new frontiers in LAG-3 biology and therapeutics. 探索LAG-3生物学和治疗学的新领域。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-06-12 DOI: 10.1016/j.tips.2025.05.008
Jun Wang, Christian Klein, Jennifer R Cochran, Jonathan Sockolosky, Shaun M Lippow
{"title":"Exploring new frontiers in LAG-3 biology and therapeutics.","authors":"Jun Wang, Christian Klein, Jennifer R Cochran, Jonathan Sockolosky, Shaun M Lippow","doi":"10.1016/j.tips.2025.05.008","DOIUrl":"10.1016/j.tips.2025.05.008","url":null,"abstract":"<p><p>Lymphocyte activation gene-3 (LAG-3) has emerged as a critical immune checkpoint receptor primarily modulating T-cell responses through distinct immune regulatory mechanisms. Recent advances have elucidated LAG-3's complex receptor-ligand interactions, structure-function relationships, and unique signaling pathways. LAG-3 antagonistic antibodies, such as relatlimab approved for melanoma, have shown promising efficacy with favorable toxicity profiles, though only in combinational therapies. While LAG-3's role in oncology continues to expand, it is also gaining recognition as a potential therapeutic target for other disorders. This review highlights recent progress in understanding LAG-3's molecular features, ligand regulation, signaling, and immune modulation mechanisms. Additionally, it explores emerging questions in oncology and the exciting potential of therapies targeting the LAG-3 pathway in autoimmune disease. A deeper understanding of LAG-3's confounding biology and disease relevance would drive the development of novel immunotherapies across broader clinical indications.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"638-652"},"PeriodicalIF":19.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Photoswitchable allosteric and dualsteric ligands in GPCR pharmacology. GPCR药理学中的光开关变构和双构配体。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-07-01 DOI: 10.1016/j.tips.2025.05.009
Silvia Mori, Damiano Arella, Michael Decker
{"title":"Photoswitchable allosteric and dualsteric ligands in GPCR pharmacology.","authors":"Silvia Mori, Damiano Arella, Michael Decker","doi":"10.1016/j.tips.2025.05.009","DOIUrl":"https://doi.org/10.1016/j.tips.2025.05.009","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) regulate numerous pathophysiological processes and have traditionally been modulated at the orthosteric site. Targeting allosteric sites offers an alternative approach that can enhance selectivity, modulate signal bias, and reduce side effects. Photopharmacology enables precise spatial and temporal drug control of receptors by light using modified drug molecules incorporating chemical photoswitches, especially azobenzenes. Allosteric and dualsteric photoswitchable ligands, the latter targeting both orthosteric and allosteric sites, are being developed - to date mainly at metabotropic glutamate (mGlu), muscarinic acetylcholine (mACh or M), and cannabinoid (CB) receptors, since their allosteric sites have been described in the most detail and with the largest number of respective allosteric ligands developed. The novel ligands can photocontrol even more refined GPCR functions, like signal bias and degrees of partial agonism. This review describes the recent development for these GPCRs in allosteric and dualsteric photoswitchable ligands, highlighting the specific challenging design, which is even more complex than for orthosteric photoswitchable ligands, since structure-activity relationships (SARs) are steep and often insufficiently described, and spacer structures strongly influence binding.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Fluorescent RNAs: new opportunities for drug discovery. 荧光rna：药物发现的新机遇。
IF 13.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-14 DOI: 10.1016/j.tips.2025.05.006
Fangting Zuo, Ziheng Gao, Xianjun Chen, Yi Yang
{"title":"Fluorescent RNAs: new opportunities for drug discovery.","authors":"Fangting Zuo, Ziheng Gao, Xianjun Chen, Yi Yang","doi":"10.1016/j.tips.2025.05.006","DOIUrl":"https://doi.org/10.1016/j.tips.2025.05.006","url":null,"abstract":"<p><p>Fluorescent RNAs (FRs), RNA mimics of fluorescent proteins (FPs), have emerged as a promising approach for tagging RNAs and investigating their complex spatiotemporal dynamics and biological functions. Moreover, FR-derived biosensors (FRBs) also provide useful tools for point-of-care testing of a wide range of targets, from small molecules, nucleic acids, and proteins to various pathogens. However, it is still unclear whether and how FRs and FRBs can be used to accelerate drug discovery. In this review article, we briefly summarize the recent advances in FRs and FRBs and focus on recent works showing how FRs and FRBs can be used during different stages of RNA and small-molecule drug discovery. Furthermore, we discuss limitations of current technologies and potential pathways for moving forward.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":13.9,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeting AMPK as a potential treatment for hepatic fibrosis in MASLD. 靶向AMPK作为MASLD肝纤维化的潜在治疗方法。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-04-28 DOI: 10.1016/j.tips.2025.03.008
Xavier Palomer, Jue-Rui Wang, Claudia Escalona, Siyuan Wu, Walter Wahli, Manuel Vázquez-Carrera
{"title":"Targeting AMPK as a potential treatment for hepatic fibrosis in MASLD.","authors":"Xavier Palomer, Jue-Rui Wang, Claudia Escalona, Siyuan Wu, Walter Wahli, Manuel Vázquez-Carrera","doi":"10.1016/j.tips.2025.03.008","DOIUrl":"10.1016/j.tips.2025.03.008","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and often progresses to hepatic fibrosis, cirrhosis, and liver failure. Despite its increasing prevalence, effective pharmacological treatments for MASLD-related fibrosis remain limited. Recent research has highlighted AMP-activated protein kinase (AMPK) as a key regulator of the processes that promote fibrogenesis, and AMPK activation shows potential in mitigating fibrosis. Advances in AMPK activators and deeper insights into their role in fibrotic pathways have recently revitalized interest in targeting AMPK for fibrosis treatment. This review discusses the molecular mechanisms linking AMPK to hepatic fibrosis and evaluates emerging AMPK-directed therapies. Furthermore, it addresses challenges in clinical translation. Importantly, we combine the latest mechanistic discoveries with recent therapeutic developments to provide a comprehensive perspective on AMPK as a target for hepatic fibrosis treatment.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"551-566"},"PeriodicalIF":19.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Developmental toxicity: artificial intelligence-powered assessments. 发育毒性：人工智能驱动的评估。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-06-01 Epub Date: 2025-05-15 DOI: 10.1016/j.tips.2025.04.005
Tong Wang, Xuelian Jia, Lauren M Aleksunes, Hui Shen, Hong-Wen Deng, Hao Zhu
{"title":"Developmental toxicity: artificial intelligence-powered assessments.","authors":"Tong Wang, Xuelian Jia, Lauren M Aleksunes, Hui Shen, Hong-Wen Deng, Hao Zhu","doi":"10.1016/j.tips.2025.04.005","DOIUrl":"10.1016/j.tips.2025.04.005","url":null,"abstract":"<p><p>Regulatory agencies require comprehensive toxicity testing for prenatal drug exposure, including new drugs in development, to reduce concerns about developmental toxicity, that is, drug-induced toxicity and adverse effects in pregnant women and fetuses. However, defining developmental toxicity endpoints and optimal analysis of associated public big data remain challenging. Recently, artificial intelligence (AI) approaches have had a critical role in analyzing complex, high-dimensional data, uncovering subtle relationships between chemical exposures and associated developmental risks. Here, we present an overview of major big data resources and data-driven models that focus on predicting various toxicity endpoints. We also highlight emerging, interpretable AI models that integrate multimodal data and domain knowledge to reveal toxic mechanisms underlying complex endpoints, and outline a potential framework that leverages multiple interpretable models to comprehensively evaluate chemical-induced developmental toxicity.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"486-502"},"PeriodicalIF":19.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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