{"title":"Emerging approaches for antagonizing the aryl hydrocarbon receptor.","authors":"Zdeněk Dvořák, Sridhar Mani, Jan Vondráček","doi":"10.1016/j.tips.2025.05.003","DOIUrl":"10.1016/j.tips.2025.05.003","url":null,"abstract":"<p><p>Antagonizing the aryl hydrocarbon receptor (AhR) is a highly pertinent pharmacotherapeutic strategy. To overcome the drawbacks of existing AhR antagonists, novel molecules that can selectively target canonical and noncanonical AhR pathways are urgently needed. Recent reports on the structures and functions of cytosolic and nuclear AhR-protein complexes have allowed for understanding structural determinants for intrinsic activity and functional selectivity of AhR ligands. This new information regarding AhR surface interactions has opened new avenues for the development of novel AhR antagonists. Achievable strategies include the negative allosteric modulation of AhR and the disruption of AhR-protein and AhR-DNA interfaces using peptidomimetics or small molecules. Here, we discuss such novel approaches that may lead to new AhR-targeted therapeutics.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"629-637"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249713","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}
{"title":"Protein acylations in cancer immunity: effects and therapeutic opportunities.","authors":"Jia-Cheng Lai, Yi-Ting Jiang, Shougeng Liu, Simeng Wang, Wei Cui, Lihui Wang","doi":"10.1016/j.tips.2025.05.011","DOIUrl":"10.1016/j.tips.2025.05.011","url":null,"abstract":"<p><p>Acylations are conserved and dynamic modifications that control various biological processes, including gene transcription and protein biology, and have been tied to diseases, such as cancers. Due to their reversible characteristic, acylations exhibit great therapeutic potential through targeting of their regulatory enzymes and proteins. Recent studies have improved our understanding of the close interplay between acylations and the tumor immune microenvironment (TIME), showing the potential to improve antitumor immune responses via acylation manipulation. Herein, we review the effects of acylations, including acetylation, lactylation, palmitoylation, and some less well-known acylations on cancer immunity, and corresponding therapeutic opportunities. Specifically, we bring into focus diverse roles of different acylation-related enzymes, metabolites, or substrates to provide insights into targeting acylations to increase antitumor immunity and generate broader research enthusiasm.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"653-673"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337035","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}
{"title":"Bright sorting yields drug-like anti-amyloid antibodies.","authors":"Bingqian Li, Pietro Sormanni","doi":"10.1016/j.tips.2025.05.013","DOIUrl":"10.1016/j.tips.2025.05.013","url":null,"abstract":"<p><p>Conformation-specific antibodies represent powerful tools for targeting pathogenic amyloid aggregates. However, the discovery of aggregate-selective antibodies with drug-like developability properties has been slow, inefficient, and difficult to generalise across different amyloid targets. The Tessier lab has developed a yeast-display screening pipeline that enables conformation-specific antibody discovery against diverse aggregated proteins.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"587-589"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317968","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}
{"title":"Limiting TDP-43 aggregation by induced recruitment to PML-NB.","authors":"Chien-Han Kao, Ruey-Hwa Chen","doi":"10.1016/j.tips.2025.05.012","DOIUrl":"10.1016/j.tips.2025.05.012","url":null,"abstract":"<p><p>TAR DNA binding protein 43 kD (TDP-43) aggregation is associated with several neurodegenerative diseases and limiting TDP-43 aggregates could offer therapeutic benefit. Recently, Wagner et al. utilized the induced proximity to PML for enhancing TDP-43 solubility under stress. Mechanistically, this strategy triggers a SUMOylation-ubiquitylation cascade on TDP-43 and the compartmentalization of TDP-43 to the promyelocytic leukemia-nuclear bodies (PML-NBs).</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"593-595"},"PeriodicalIF":13.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249714","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}
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":13.9,"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}
{"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":13.9,"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}
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":13.9,"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}
{"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":13.9,"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}
{"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}