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Annual review of pharmacology and toxicology最新文献

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Beyond Catalytic Inhibition: The Evolving Landscape of PARP Pharmacology. 超越催化抑制：PARP药理学的发展前景。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-08-10 DOI: 10.1146/annurev-pharmtox-060425-062841
Michael C Owens, Anthony K L Leung
{"title":"Beyond Catalytic Inhibition: The Evolving Landscape of PARP Pharmacology.","authors":"Michael C Owens, Anthony K L Leung","doi":"10.1146/annurev-pharmtox-060425-062841","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060425-062841","url":null,"abstract":"<p><p>Since the identification of PARP1/2 as synthetic lethal targets in BRCA-deficient breast cancer and the subsequent approval of catalytic domain-targeting PARP inhibitors, the landscape of PARP inhibitors has expanded to encompass a broader chemical tool kit. Beyond PARP1/2's canonical role in DNA repair, PARP inhibitors have revealed context-dependent PARP functions in anticancer immunity, viral infection, neurodegeneration, and cellular organization. These discoveries have motivated new strategies that extend past targeting catalytic domains. In this review, we highlight three emerging directions: (<i>a</i>) biological insights revealed by PARP1/2 inhibitors in oncology and other settings, (<i>b</i>) progress in developing inhibitors against PARP family members beyond PARP1/2, and (<i>c</i>) approaches that target noncatalytic domains or modulate PARP function through mechanisms such as interface disruption and targeted degradation. We conclude by outlining key next steps for advancing PARP pharmacology, including substrate mapping, utilizing rational polypharmacology, targeting ADP-ribose readers and erasers, and expanding structural coverage of PARP family proteins.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705238","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
Vesicular Monoamine Transporters at the Crossroads of Structure and Function: Advances, Challenges, and Future Perspectives. 囊泡单胺转运蛋白在结构和功能的十字路口：进展、挑战和未来展望。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-08-07 DOI: 10.1146/annurev-pharmtox-060225-123449
Kai H Lange, Michael P Dalton, Suraj Kumar Mandal, Jonathan A Coleman
{"title":"Vesicular Monoamine Transporters at the Crossroads of Structure and Function: Advances, Challenges, and Future Perspectives.","authors":"Kai H Lange, Michael P Dalton, Suraj Kumar Mandal, Jonathan A Coleman","doi":"10.1146/annurev-pharmtox-060225-123449","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060225-123449","url":null,"abstract":"<p><p>Monoaminergic signaling controls many aspects of human physiology, including autonomic responses, movement, and emotion. The vesicular monoamine transporters (VMAT1 and VMAT2) sequester monoamines into synaptic vesicles within the central and peripheral nervous system. Dysregulation of VMAT function contributes to neuropsychiatric and neurodegenerative disorders, including Parkinson's disease, depression, and psychostimulant substance abuse. Clinically, VMATs are targeted by the inhibitors tetrabenazine and reserpine, used to treat hyperkinetic movement disorders and hypertension, respectively, while amphetamines exploit VMAT2-mediated dopamine efflux to treat ADHD. Emerging VMAT2-selective compounds such as lobeline derivatives and GZ-11610 attenuate psychostimulant reinforcement. Tricyclic antidepressants upregulate VMAT2 function and rescue disease-causing variants, highlighting VMAT2 as a promising therapeutic target. Despite their importance, the molecular mechanisms driving proton-coupled transport, inhibition, and psychostimulant action remain poorly understood. This review summarizes current biochemical, structural, and functional insights into VMATs, highlighting proton coupling, transport kinetics, inhibition mechanisms, unresolved questions, and future research directions.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688417","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
The Pharmacology of CAR T Cell Therapy for Autoimmune Disease. CAR - T细胞治疗自身免疫性疾病的药理学研究
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-08-03 DOI: 10.1146/annurev-pharmtox-060225-095155
Juliang Qin, Guangyu Zhang, Ning Zhao, Bing Du, Mingyao Liu
{"title":"The Pharmacology of CAR T Cell Therapy for Autoimmune Disease.","authors":"Juliang Qin, Guangyu Zhang, Ning Zhao, Bing Du, Mingyao Liu","doi":"10.1146/annurev-pharmtox-060225-095155","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060225-095155","url":null,"abstract":"<p><p>For decades, autoimmune disease treatment depended on long-term immunosuppression, which seldom yields lasting immune tolerance and carries cumulative toxic risks. Recent cell therapies, including chimeric antigen receptor (CAR) T cells, regulatory T cells, and mesenchymal stromal cells, have induced deep remission in refractory diseases, often persisting after treatment withdrawal and indicating benefits beyond short-term inflammation suppression. However, traditional dose-exposure-response pharmacokinetic/pharmacodynamic frameworks are insufficient to account for the in vivo expansion, trafficking, and phenotypic evolution of living cellular products. Here we propose that, in autoimmune diseases, cell-based therapies exemplified by CAR T cells should be reframed from exposure-control pharmacology to state-transition pharmacology. Through endogenous expansion and immune networks, therapeutic cells may shift the immune system from a pathological toward a tolerant steady state. Because toxicities may reflect the amplification or persistence of intended mechanisms, future work requires quantitative metrics of immune state transitions and programmable strategies for precise functional control.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668375","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
Sex Differences in Secondary Prevention Pharmacotherapy for Acute Coronary Syndromes. 急性冠脉综合征二级预防药物治疗的性别差异
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-07-21 DOI: 10.1146/annurev-pharmtox-101325-092507
Andrew J Sullivan, Margaret Siu, Krishnaraj Rathod, Amrita Ahluwalia
{"title":"Sex Differences in Secondary Prevention Pharmacotherapy for Acute Coronary Syndromes.","authors":"Andrew J Sullivan, Margaret Siu, Krishnaraj Rathod, Amrita Ahluwalia","doi":"10.1146/annurev-pharmtox-101325-092507","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-101325-092507","url":null,"abstract":"<p><p>Global data demonstrate that women have worse outcomes following acute coronary syndromes (ACS) compared to men. Routine follow-up care for ACS involves optimal medical therapy (OMT) to reduce the risk of future adverse cardiovascular outcomes; however, women are both less likely to receive OMT and underrepresented in cardiovascular clinical trials; thus, a sex bias exists in the evidence for many OMT drugs. In this review we examine sex-specific data for OMT, exploring sex differences in the pharmacology and clinical efficacy of these drugs. We outline various sex differences in the pharmacodynamics and pharmacokinetics of OMT drugs, which do not appear to result in convincing differences in efficacy. However, women are at increased risk of drug-related side effects, which has important implications for adherence and discontinuation. Sex-specific guidance is needed for current OMT medications to address differences in prescribing and side effect profiles. Understanding the sex-specific pharmacology of OMT is key to providing more personalized care.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547099","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
Therapeutics for Alcohol-Associated Liver Disease. 酒精相关性肝病的治疗
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-07-20 DOI: 10.1146/annurev-pharmtox-060225-121425
Marta Melis, Hamza Dahshi, Laura E Nagy
{"title":"Therapeutics for Alcohol-Associated Liver Disease.","authors":"Marta Melis, Hamza Dahshi, Laura E Nagy","doi":"10.1146/annurev-pharmtox-060225-121425","DOIUrl":"10.1146/annurev-pharmtox-060225-121425","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) is a major driver of morbidity and mortality globally, especially in its most severe phenotypes, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and hepatocellular carcinoma. With no US Food and Drug Administration-approved therapies to improve ALD, there is an unmet clinical need to better define the pathophysiology of early and severe liver disease. Recent improvements in preclinical models have furthered our understanding of the mechanisms of disease in advanced ALD. In this review, our focus is on current progress in identifying therapeutic targets utilizing preclinical models and reporting the rationale for and current status of ongoing clinical trials that aim to develop effective therapies to slow the progression of earlier stages of ALD and especially improve survival in severe AH.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534841","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
Proteome-Wide Binding Affinity Profiling. 蛋白质组结合亲和分析。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-07-06 DOI: 10.1146/annurev-pharmtox-060225-120320
Noah Yardeny, Jacob B Geri
{"title":"Proteome-Wide Binding Affinity Profiling.","authors":"Noah Yardeny, Jacob B Geri","doi":"10.1146/annurev-pharmtox-060225-120320","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060225-120320","url":null,"abstract":"<p><p>Selective interactions between ligands and protein targets are fundamental to normal biological processes and drug action, and the strength of these interactions is a key metric that defines their functions and disease relevance. Recently introduced methods couple ligand-protein interactions to mass spectrometry-proteomic readouts, enabling the measurement of proteome-wide binding affinity profiles. Here, we review the state of affinity profiling technology, focusing on three key approaches: (<i>a</i>) protein stability-based methods, which detect ligand-induced stabilization against thermal or chemical denaturation; (<i>b</i>) proteolytic resistance-based methods, which infer protein binding through altered susceptibility to enzymatic digestion; and (<i>c</i>) methods that use derivatized probes to capture and enrich ligand-protein complexes.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395799","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
A Change of Mind: Targeting Amyloid-β with Better Safety Profile. 想法的改变：靶向淀粉样蛋白β具有更好的安全性。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-01-01 Epub Date: 2025-06-25 DOI: 10.1146/annurev-pharmtox-062124-113434
Katelynn E Krick, Donna M Wilcock
{"title":"A Change of Mind: Targeting Amyloid-β with Better Safety Profile.","authors":"Katelynn E Krick, Donna M Wilcock","doi":"10.1146/annurev-pharmtox-062124-113434","DOIUrl":"10.1146/annurev-pharmtox-062124-113434","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative disease that leads to cognitive decline and dementia. Over the past two decades, many scientists have contributed to the discovery of therapeutics that target amyloid-beta (Aβ) to slow the progression of AD. These discoveries have led to the development of the first disease-modifying therapeutics in AD, though these come with the risk of side effects known as amyloid-related imaging abnormalities (ARIA). There are currently many exciting studies and trials working to mitigate ARIA risk that range from modifying antibodies to potential combination therapeutics. This review addresses some of the ongoing research areas for improving safety in Aβ targeting as well as clinical considerations for current patient treatment.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"391-403"},"PeriodicalIF":19.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493729","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
Introduction to the Theme "New Approaches, Technology, and Techniques That Advance Pharmacology and Toxicology". 主题为“促进药理学和毒理学发展的新方法、新技术和新技术”的导论。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-01-01 Epub Date: 2025-09-29 DOI: 10.1146/annurev-pharmtox-082525-041413
Paul A Insel, Amrita Ahluwalia, Susan G Amara
{"title":"Introduction to the Theme \"New Approaches, Technology, and Techniques That Advance Pharmacology and Toxicology\".","authors":"Paul A Insel, Amrita Ahluwalia, Susan G Amara","doi":"10.1146/annurev-pharmtox-082525-041413","DOIUrl":"10.1146/annurev-pharmtox-082525-041413","url":null,"abstract":"<p><p>Volume 66 of the <i>Annual Review of Pharmacology and Toxicology</i> includes numerous articles that reveal evolving ideas and insights in pharmacology and toxicology. The major theme is new approaches, technology and techniques. New ideas include the use of systems biology, multiomics, and artificial intelligence to support wellness, prevention, early detection of disease, and precision medicine. Other reviews highlight new ideas and approaches to treat infectious diseases, including the repurposing of drugs approved for other indications and long-acting therapeutics. Related reviews emphasize aspects of global health. One review discusses psychedelics as therapeutics. Several reviews discuss advances in drug discovery modalities. Others relate to a variety of topics in toxicology, including aspects of mitochondrial biology, e-cigarettes, air pollution, microplastics, and nanoplastics. These reviews and others in this volume inform readers about recent advances in pharmacology and toxicology and show how both specialties continue to be vital for improving health and safety globally.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"1-5"},"PeriodicalIF":19.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190596","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
Navigating the Computational Landscape for Drug Repurposing. 导航药物再利用的计算景观。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-01-01 DOI: 10.1146/annurev-pharmtox-121924-042636
Andrea Álvarez-Pérez, Lucía Prieto-Santamaría, Ana I Casas, Joseph Loscalzo, Alejandro Rodríguez-González
{"title":"Navigating the Computational Landscape for Drug Repurposing.","authors":"Andrea Álvarez-Pérez, Lucía Prieto-Santamaría, Ana I Casas, Joseph Loscalzo, Alejandro Rodríguez-González","doi":"10.1146/annurev-pharmtox-121924-042636","DOIUrl":"10.1146/annurev-pharmtox-121924-042636","url":null,"abstract":"<p><p>Giving old drugs new uses, a process known as drug repurposing, is an attractive strategy for finding therapeutic candidates for a wide number of diseases. In this context, data-driven approaches have emerged as a suitable framework to target this challenge. From molecular docking and network-based methods to omics data integration, computational techniques give invaluable insights into drug repurposing research. In the present review, we describe these methodologies and knowledge-based resources, also emphasizing the new horizons that artificial intelligence and large language models are revealing. A set of case studies illuminate the practical applications of these computational approaches to the identification of repurposing opportunities. By addressing a set of key challenges and proposing future directions, this review aims to be a resource for researchers navigating the multifaceted landscape of computational drug repurposing.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"66 1","pages":"149-170"},"PeriodicalIF":19.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040378","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
Biased Signaling in Psychedelic Action. 致幻剂作用中的偏倚信号。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-01-01 Epub Date: 2025-08-12 DOI: 10.1146/annurev-pharmtox-062124-012545
Daniel Wacker, John D McCorvy
{"title":"Biased Signaling in Psychedelic Action.","authors":"Daniel Wacker, John D McCorvy","doi":"10.1146/annurev-pharmtox-062124-012545","DOIUrl":"10.1146/annurev-pharmtox-062124-012545","url":null,"abstract":"<p><p>Psychedelics show tremendous promise for treating psychiatric disorders and other illnesses, including pain and migraine. Despite decades of research, there is uncertainty which signaling mechanisms are necessary for rapid-acting and durable therapeutic effects of psychedelics. Although activation of the serotonin 5-HT<sub>2A</sub> receptor is critical for their psychopharmacological effects, the precise signaling pathways and receptor conformations responsible are still under investigation. This review summarizes progress in studying 5-HT<sub>2A</sub> signaling mechanisms and recent developments in the discovery of biased agonist tool compounds to disentangle therapeutic from adverse effects. Moreover, we review insights from structural studies regarding the design of psychedelic-derived compounds with tailored pharmacology and briefly discuss other 5-HT receptors that may be important for shaping therapeutic effects. Finally, by drawing parallels between 5-HT<sub>2A</sub> biased signaling and the opioid field, we conclude with lessons learned and discuss the need for more rigor and reproducibility to facilitate the development of novel psychedelic-based pharmacotherapies.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"241-260"},"PeriodicalIF":19.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833806","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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