Pub Date : 2024-09-01Epub Date: 2024-07-29DOI: 10.1016/j.tips.2024.07.002
Kilian Wagner, Peter J Siska
Cellular therapies against solid tumors face three major barriers: low persistence, insufficient specificity, and high costs. In a recent study, Pal et al. tackle these challenges in kidney cancer by using novel, 'persistence-tuned' allogeneic chimeric antigen receptor (CAR) T cells directed against a stable antigen.
{"title":"'Living drugs' target CD70 in advanced renal tumors.","authors":"Kilian Wagner, Peter J Siska","doi":"10.1016/j.tips.2024.07.002","DOIUrl":"10.1016/j.tips.2024.07.002","url":null,"abstract":"<p><p>Cellular therapies against solid tumors face three major barriers: low persistence, insufficient specificity, and high costs. In a recent study, Pal et al. tackle these challenges in kidney cancer by using novel, 'persistence-tuned' allogeneic chimeric antigen receptor (CAR) T cells directed against a stable antigen.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856570","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}
Signal transducer and activator of transcription 3 (STAT3) has been widely considered as a therapeutic target for various diseases, especially tumors. Thus far, several STAT3 inhibitors have been advanced to clinical trials; however, the development of STAT3 inhibitors is hindered by numerous dilemmas. Fortunately, STAT3 degraders represent an alternative and promising strategy to block STAT3, attracting extensive research interest. Here, we analyze the recent advancements of STAT3 degraders, including proteolysis targeting chimeras (PROTACs) and small-molecule natural products, focusing on their structures, mechanisms, and biological activities. We discuss the potential opportunities and challenges for developing STAT3 degraders. It is hoped that this Review will provide insights into the discovery of potent STAT3-targeting drugs.
{"title":"Targeting the STAT3 pathway with STAT3 degraders.","authors":"Zhijie Wang, Xiaotong Liao, Haiqi He, Xia Guo, Jianjun Chen","doi":"10.1016/j.tips.2024.07.003","DOIUrl":"10.1016/j.tips.2024.07.003","url":null,"abstract":"<p><p>Signal transducer and activator of transcription 3 (STAT3) has been widely considered as a therapeutic target for various diseases, especially tumors. Thus far, several STAT3 inhibitors have been advanced to clinical trials; however, the development of STAT3 inhibitors is hindered by numerous dilemmas. Fortunately, STAT3 degraders represent an alternative and promising strategy to block STAT3, attracting extensive research interest. Here, we analyze the recent advancements of STAT3 degraders, including proteolysis targeting chimeras (PROTACs) and small-molecule natural products, focusing on their structures, mechanisms, and biological activities. We discuss the potential opportunities and challenges for developing STAT3 degraders. It is hoped that this Review will provide insights into the discovery of potent STAT3-targeting drugs.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907806","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}
Pub Date : 2024-09-01Epub Date: 2024-08-09DOI: 10.1016/j.tips.2024.07.001
Raphael R Fagundes, Arnaud Zaldumbide, Cormac T Taylor
Type 1 diabetes (T1D) is a common autoimmune disease in which dysregulated glucose metabolism is a key feature. T1D is both poorly understood and in need of improved therapeutics. Hypoxia is frequently encountered in multiple tissues in T1D patients including the pancreas and sites of diabetic complications. Hypoxia-inducible factor (HIF)-1, a ubiquitous master regulator of the adaptive response to hypoxia, promotes glucose metabolism through transcriptional and non-transcriptional mechanisms and alters disease progression in multiple preclinical T1D models. However, how HIF-1 activation in β-cells of the pancreas and immune cells (two key cell types in T1D) ultimately affects disease progression remains controversial. We discuss recent advances in our understanding of the role of hypoxia/HIF-1-induced glycolysis in T1D and explore the possible use of drugs targeting this pathway as potential new therapeutics.
{"title":"Role of hypoxia-inducible factor 1 in type 1 diabetes.","authors":"Raphael R Fagundes, Arnaud Zaldumbide, Cormac T Taylor","doi":"10.1016/j.tips.2024.07.001","DOIUrl":"10.1016/j.tips.2024.07.001","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is a common autoimmune disease in which dysregulated glucose metabolism is a key feature. T1D is both poorly understood and in need of improved therapeutics. Hypoxia is frequently encountered in multiple tissues in T1D patients including the pancreas and sites of diabetic complications. Hypoxia-inducible factor (HIF)-1, a ubiquitous master regulator of the adaptive response to hypoxia, promotes glucose metabolism through transcriptional and non-transcriptional mechanisms and alters disease progression in multiple preclinical T1D models. However, how HIF-1 activation in β-cells of the pancreas and immune cells (two key cell types in T1D) ultimately affects disease progression remains controversial. We discuss recent advances in our understanding of the role of hypoxia/HIF-1-induced glycolysis in T1D and explore the possible use of drugs targeting this pathway as potential new therapeutics.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914115","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}
Pub Date : 2024-09-01Epub Date: 2024-08-23DOI: 10.1016/j.tips.2024.07.007
Ivan Talucci, Hans M Maric
Autoantibody binding has a central role in autoimmune diseases and has also been linked to cancer, infections, and behavioral disorders. Autoimmune neurological diseases remain misclassified also due to an incomplete understanding of the underlying disease-specific epitopes. Such epitopes are crucial for both pathology and diagnosis, but have historically been overlooked. Recent technological advancements have enabled the exploration of these epitopes, potentially opening novel clinical avenues. The precise identification of novel B and T cell epitopes and their autoreactivity has led to the discovery of autoantigen-specific biomarkers for patients at high risk of autoimmune neurological diseases. In this review, we propose utilizing newly available synthetic and cellular-surface display technologies and guide epitope-focused studies to unlock the potential of disease-specific epitopes for improving diagnosis and treatments. Additionally, we offer recommendations to guide emerging epitope-focused studies to broaden the current landscape.
自身抗体结合在自身免疫性疾病中起着核心作用,同时也与癌症、感染和行为紊乱有关。自身免疫性神经系统疾病仍然存在分类错误,这也是由于对潜在的疾病特异性表位了解不全面。这些表位对病理和诊断都至关重要,但历来被忽视。最近的技术进步使得对这些表位的探索成为可能,从而开辟了新的临床途径。对新型 B 细胞和 T 细胞表位及其自身反应性的精确鉴定,为自身免疫性神经疾病高危患者发现了自身抗原特异性生物标志物。在这篇综述中,我们建议利用最新的合成和细胞表面显示技术,指导以表位为重点的研究,发掘疾病特异性表位的潜力,以改善诊断和治疗。此外,我们还提出了指导新兴表位研究的建议,以拓宽目前的研究领域。
{"title":"Epitope landscape in autoimmune neurological disease and beyond.","authors":"Ivan Talucci, Hans M Maric","doi":"10.1016/j.tips.2024.07.007","DOIUrl":"10.1016/j.tips.2024.07.007","url":null,"abstract":"<p><p>Autoantibody binding has a central role in autoimmune diseases and has also been linked to cancer, infections, and behavioral disorders. Autoimmune neurological diseases remain misclassified also due to an incomplete understanding of the underlying disease-specific epitopes. Such epitopes are crucial for both pathology and diagnosis, but have historically been overlooked. Recent technological advancements have enabled the exploration of these epitopes, potentially opening novel clinical avenues. The precise identification of novel B and T cell epitopes and their autoreactivity has led to the discovery of autoantigen-specific biomarkers for patients at high risk of autoimmune neurological diseases. In this review, we propose utilizing newly available synthetic and cellular-surface display technologies and guide epitope-focused studies to unlock the potential of disease-specific epitopes for improving diagnosis and treatments. Additionally, we offer recommendations to guide emerging epitope-focused studies to broaden the current landscape.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056599","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}
Pub Date : 2024-09-01Epub Date: 2024-08-24DOI: 10.1016/j.tips.2024.07.004
Jéssica Lopes-Nunes, Paula A Oliveira, Carla Cruz
Human papillomaviruses (HPVs) are well-known causative agents of several cancers, yet selective therapies remain under investigation. Nanoparticles, for instance, are emerging as promising solutions to enhance the delivery and efficacy of therapeutic approaches. Despite the increasing number of nanotherapies offering advantages over current treatments, only one has advanced to clinical trials. This review highlights recent advances in nanotherapies for HPV-associated cancers, focusing on the delivery of small molecules, gene-targeted therapies, and vaccines. Some of the challenges faced in nanotherapies translation for clinical application are discussed, emphasizing the most used preclinical models that fail to accurately predict human responses, thereby hindering proper evaluation of nanotherapies. Additionally, we explore and discuss alternative promising new preclinical models that could pave the way for more effective nanotherapeutic evaluations.
{"title":"Nanotherapy for human papillomavirus-associated cancers: breakthroughs and challenges.","authors":"Jéssica Lopes-Nunes, Paula A Oliveira, Carla Cruz","doi":"10.1016/j.tips.2024.07.004","DOIUrl":"10.1016/j.tips.2024.07.004","url":null,"abstract":"<p><p>Human papillomaviruses (HPVs) are well-known causative agents of several cancers, yet selective therapies remain under investigation. Nanoparticles, for instance, are emerging as promising solutions to enhance the delivery and efficacy of therapeutic approaches. Despite the increasing number of nanotherapies offering advantages over current treatments, only one has advanced to clinical trials. This review highlights recent advances in nanotherapies for HPV-associated cancers, focusing on the delivery of small molecules, gene-targeted therapies, and vaccines. Some of the challenges faced in nanotherapies translation for clinical application are discussed, emphasizing the most used preclinical models that fail to accurately predict human responses, thereby hindering proper evaluation of nanotherapies. Additionally, we explore and discuss alternative promising new preclinical models that could pave the way for more effective nanotherapeutic evaluations.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056600","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}
Pub Date : 2024-08-08DOI: 10.1016/s0165-6147(24)00156-1
No Abstract
无摘要
{"title":"Subscription and Copyright Information","authors":"","doi":"10.1016/s0165-6147(24)00156-1","DOIUrl":"https://doi.org/10.1016/s0165-6147(24)00156-1","url":null,"abstract":"No Abstract","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141946201","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}
Pub Date : 2024-08-08DOI: 10.1016/s0165-6147(24)00152-4
No Abstract
无摘要
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/s0165-6147(24)00152-4","DOIUrl":"https://doi.org/10.1016/s0165-6147(24)00152-4","url":null,"abstract":"No Abstract","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141946134","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}
Pub Date : 2024-08-01Epub Date: 2024-07-16DOI: 10.1016/j.tips.2024.06.004
Qi Gao, Onur Cil
Magnesium (Mg2+) is a commonly used dietary supplement for the prevention and treatment of diseases. However, the efficacy and mechanisms of action of Mg2+ in most diseases have been controversial because of conflicting findings in earlier studies. Recent clinical and preclinical studies provide novel insights into the use of Mg2+ for the treatment and prevention of diseases affecting different organ systems. In this review, we provide an overview of recent clinical evidence for, and controversies over, the medical benefits of Mg2+. In addition, we critically discuss recent advances in understanding the mechanisms of action of Mg2+, which could enable the development of novel targeted therapies.
{"title":"Magnesium for disease treatment and prevention: emerging mechanisms and opportunities.","authors":"Qi Gao, Onur Cil","doi":"10.1016/j.tips.2024.06.004","DOIUrl":"10.1016/j.tips.2024.06.004","url":null,"abstract":"<p><p>Magnesium (Mg<sup>2+</sup>) is a commonly used dietary supplement for the prevention and treatment of diseases. However, the efficacy and mechanisms of action of Mg<sup>2+</sup> in most diseases have been controversial because of conflicting findings in earlier studies. Recent clinical and preclinical studies provide novel insights into the use of Mg<sup>2+</sup> for the treatment and prevention of diseases affecting different organ systems. In this review, we provide an overview of recent clinical evidence for, and controversies over, the medical benefits of Mg<sup>2+</sup>. In addition, we critically discuss recent advances in understanding the mechanisms of action of Mg<sup>2+</sup>, which could enable the development of novel targeted therapies.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634628","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}
Pub Date : 2024-08-01Epub Date: 2024-07-22DOI: 10.1016/j.tips.2024.06.003
Bernd J Zünkler
Numerous non-cardiovascular drugs have a potential to induce life-threatening torsades de pointes (TdP) ventricular cardiac arrhythmias by blocking human ether-à-go-go-related gene (hERG) currents via binding to the channel's inner cavity. Identification of the hERG current-inhibiting properties of candidate drugs is performed focusing on binding sites in the channel pore. It has been suggested that biologicals have a low likelihood of hERG current inhibition, since their poor diffusion across the plasma membrane prevents them from reaching the binding site in the channel pore. However, biologicals could influence hERG channel function by binding to 'unconventional' noncanonical binding sites. This Opinion gives an overview on noncanonical blockers of hERG channels that might be of relevance for the assessment of the possible torsadogenic potential of macromolecular therapeutics.
{"title":"Multiple hERG channel blocking pathways: implications for macromolecules.","authors":"Bernd J Zünkler","doi":"10.1016/j.tips.2024.06.003","DOIUrl":"10.1016/j.tips.2024.06.003","url":null,"abstract":"<p><p>Numerous non-cardiovascular drugs have a potential to induce life-threatening torsades de pointes (TdP) ventricular cardiac arrhythmias by blocking human ether-à-go-go-related gene (hERG) currents via binding to the channel's inner cavity. Identification of the hERG current-inhibiting properties of candidate drugs is performed focusing on binding sites in the channel pore. It has been suggested that biologicals have a low likelihood of hERG current inhibition, since their poor diffusion across the plasma membrane prevents them from reaching the binding site in the channel pore. However, biologicals could influence hERG channel function by binding to 'unconventional' noncanonical binding sites. This Opinion gives an overview on noncanonical blockers of hERG channels that might be of relevance for the assessment of the possible torsadogenic potential of macromolecular therapeutics.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752917","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}
Pub Date : 2024-08-01Epub Date: 2024-06-08DOI: 10.1016/j.tips.2024.05.010
Jürgen Wess, Liu Liu
The M2 muscarinic receptor (M2R) is a prototypic class A G protein-coupled receptor (GPCR). Interestingly, Fasciani et al. recently identified an internal translation start site within the M2 receptor mRNA, directing the expression of a C-terminal receptor fragment. Elevated during cellular stress, this polypeptide localizes to mitochondria where it inhibits oxidative phosphorylation.
M2 muscarinic 受体(M2R)是 A 类 G 蛋白偶联受体(GPCR)的原型。有趣的是,Fasciani 等人最近在 M2 受体 mRNA 中发现了一个内部翻译起始位点,可引导 C 端受体片段的表达。这种多肽在细胞受压时会升高,并定位到线粒体,抑制线粒体的氧化磷酸化。
{"title":"A novel function of the M<sub>2</sub> muscarinic receptor.","authors":"Jürgen Wess, Liu Liu","doi":"10.1016/j.tips.2024.05.010","DOIUrl":"10.1016/j.tips.2024.05.010","url":null,"abstract":"<p><p>The M<sub>2</sub> muscarinic receptor (M2R) is a prototypic class A G protein-coupled receptor (GPCR). Interestingly, Fasciani et al. recently identified an internal translation start site within the M<sub>2</sub> receptor mRNA, directing the expression of a C-terminal receptor fragment. Elevated during cellular stress, this polypeptide localizes to mitochondria where it inhibits oxidative phosphorylation.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296744","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}