ACS Chemical Biology最新文献

{"title":"Discovery of IHMT-15130 as a Highly Potent Irreversible BMX Inhibitor for the Treatment of Myocardial Hypertrophy and Remodeling.","authors":"Shuang Qi, Jiangyan Cao, Ting Wu, Chenliang Shi, Junjie Wang, Beilei Wang, Ziping Qi, Hong Wu, Yun Wu, Aoli Wang, Jing Liu, Wenchao Wang, Qingsong Liu","doi":"10.1021/acschembio.4c00875","DOIUrl":"https://doi.org/10.1021/acschembio.4c00875","url":null,"abstract":"<p><p>Cardiac hypertrophy is usually accompanied by many forms of heart disease, including hypertension, vascular disease, ischemic disease, and heart failure, and thus effectively predicts the increased cardiovascular morbidity and mortality. Bone marrow kinase in chromosome X (BMX) has been reported to be the major signaling transduction protein in cardiac arterial endothelial cells and is thought to be involved in the pathology of cardiac hypertrophy. We report here the discovery of a potent irreversible BMX kinase inhibitor, IHMT-15130, which covalently targets cysteine 496 of BMX and exhibits potent inhibitory activity against BMX kinase (IC₅₀: 1.47 ± 0.07 nM). Compared to recently approved BTK/BMX dual inhibitor Ibrutinib, IHMT-15130 displayed selectivity over CSK kinase (IC₅₀ > 25,000 nM), targeting of which may cause severe atrial fibrillation and bleeding. IHMT-15130 effectively reduced the secretion of inflammatory cytokines, inhibited the inflammatory signaling pathway in vitro and in vivo, and alleviated angiotensin II (Ang II)-induced myocardial hypertrophy in a murine model. This study provides further experimental evidence for the application of BMX kinase inhibitors in the treatment of cardiac hypertrophy.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trihydroxybenzaldoximes are Redox Cycling Inhibitors of ThDP-Dependent DXP Synthase.","authors":"Charles R Nosal, Ananya Majumdar, Netzahualcóyotl Arroyo-Currás, Caren L Freel Meyers","doi":"10.1021/acschembio.5c00025","DOIUrl":"10.1021/acschembio.5c00025","url":null,"abstract":"<p><p>Pathogenic bacteria must swiftly adapt to dynamic infection environments in order to survive and colonize in the host. 1-Deoxy-d-xylulose-5-phosphate synthase (DXPS) is thought to play a critical role in bacterial adaptation during infection and is a promising drug target. DXPS utilizes a thiamine diphosphate (ThDP) cofactor to catalyze the decarboxylative condensation of pyruvate and d-glyceraldehyde-3-phosphate (d-GAP) to form DXP, a precursor to isoprenoids and B vitamins. DXPS follows a ligand-gated mechanism in which pyruvate reacts with ThDP to form a long-lived lactyl-ThDP (LThDP) adduct which is coordinated by an active-site network of residues. d-GAP binding ostensibly disrupts this network to activate LThDP for decarboxylation. Our lab previously reported trihydroxybenzaldoxime inhibitors which are competitive with respect to d-GAP, and uncompetitive with respect to pyruvate, suggesting they bind after E-LThDP complex formation. Here, we conducted mechanistic studies to determine if these compounds inhibit DXPS by preventing LThDP activation or if they act as inducers of LThDP activation. We discovered that the catechol moiety of the trihydroxybenzaldoxime scaffold undergoes oxidation under alkaline aerobic conditions, and inhibitory potency is reduced under oxygen restriction. Leveraging long-range ¹H-¹⁵N HSQC NMR and electrochemical measurements, we demonstrated that the oxidized form of the trihydroxybenzaldoxime induces LThDP decarboxylation and accepts electrons from the resulting carbanion, resulting in reduction to the catechol and formation of acetyl-ThDP which hydrolyzes to form acetate. Under aerobic conditions the catechol is reoxidized. Thus, these compounds act as redox cycling, substrate-wasting inhibitors of DXP formation. These findings uncover a novel activity and mechanism of DXPS inhibition which may have implications for DXPS-mediated redox activity in bacteria. Further exploration of redox active DXPS probes may provide new insights for inhibition strategies and selective probe development.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Synthetic Lethality Screens Identify Selective Drug Combinations against <i>Pseudomonas aeruginosa</i>.","authors":"Ellysia N Overton, Yifan Zhang, Wabathi Ngecu, Mohammad R Seyedsayamdost","doi":"10.1021/acschembio.5c00076","DOIUrl":"10.1021/acschembio.5c00076","url":null,"abstract":"<p><p>The emergence of bacterial ESKAPE pathogens presents a formidable challenge to global health, necessitating the development of innovative strategies for antibiotic discovery. Here, we leverage chemical synthetic lethality to locate therapeutic combinations of small molecules against multidrug-resistant <i>Pseudomonas aeruginosa</i>. Using a transposon screen, we identify PyrD as a target for sensitizing <i>P. aeruginosa</i> to subinhibitory doses of ceftazidime. High-throughput inhibitor screens identify two PyrD inhibitors, nordihydroguaiaretic acid (NDGA) and chlorhexidine (CHX), each of which does not significantly affect growth in isolation but exhibits chemical synthetic lethality when combined with low-dose ceftazidime. Downstream biochemical studies elucidate the mechanism of inhibition by NDGA and CHX. Remarkably, this combination is toxic to <i>P. aeruginosa</i> but leaves commensal bacteria, which are more susceptible to antibiotics, unscathed. Aside from advancing drug combinations that may be explored further in the future, our results offer a new approach for devising potent and specific drug combinations against recalcitrant pathogens.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1077-1086"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Comprehensive Screening and Assessment Assays for Small-Molecule Ligands of MALAT1 lncRNA.","authors":"Mélanie Pernak, Claire Fleurisson, Cécile Delorme, Roba Moumné, Erica Benedetti, Laurent Micouin, Stéphane Azoulay, Yann Foricher, Maria Duca","doi":"10.1021/acschembio.5c00061","DOIUrl":"10.1021/acschembio.5c00061","url":null,"abstract":"<p><p>RNA targeting represents an original and promising approach to the discovery of new therapeutic tools against numerous diseases. The majority of intracellular RNAs are noncoding RNAs that play key regulatory functions in many physiological processes. Among these RNAs, long noncoding RNAs (lncRNAs) constitute the largest class of noncoding transcripts and have been shown to play important functional roles in development and disease processes. In this work, we developed a set of biochemical assays for the discovery of efficient small-molecule lncRNA ligands selective for their target, focusing on MALAT1 lncRNA. The latter bears a particular structure including a triple helical region important for its function, and it has been linked to cancer cells' proliferation. However, its role in cancer still needs to be completely elucidated. The application of these assays to an original library of RNA binders allowed for the discovery of unprecedented ligands of the MALAT1 triple helix able to inhibit and destabilize the triple helical MALAT1 structure. The set of screening and validation assays developed could find application in the discovery of new MALAT1 binders, and the new chemical scaffolds discovered in this study represent promising chemical probes for the study of the biological role of MALAT1 in disease.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1068-1076"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Pseudomonas Virulence</i> <i>Factor</i> Produces Autoinducer (<i>S</i>)-Valdiazen.","authors":"Drake M Crawford, Jack C Roche, Qiang Guo, Christopher Brache, Bo Li","doi":"10.1021/acschembio.4c00837","DOIUrl":"10.1021/acschembio.4c00837","url":null,"abstract":"<p><p><i>Pseudomonas virulence</i> <i>factor</i> (<i>pvf</i>) produces an autoinducing small-molecule signal that regulates bacterial cell-to-cell communication and virulence. While genes like <i>pvf</i> have been linked to the production of small molecules containing a diazeniumdiolate group, the specific chemical signal produced by <i>pvf</i> had not been identified. In this study, we reveal that (<i>S</i>)-valdiazen is the autoinducer produced by <i>pvf</i> in <i>Pseudomonas entomophila</i>, a model for pathogen-host interactions. The (<i>S</i>)-configuration is crucial for the signaling activity of valdiazen at physiological concentrations. We also define the (<i>S</i>)-stereochemistry of leudiazen, a similar signal produced by the plant pathogen <i>Pseudomonas syringae</i>. Using <i>pvf</i> genes needed for (<i>S</i>)-valdiazen signaling and production in <i>P. entomophila</i>, we bioinformatically identified 5383 bacterial organisms that may produce diazeniumdiolate signals. Signaling activity of valdiazen can be quenched by potassium permanganate, which oxidizes the diazeniumdiolate moiety. Identification of (<i>S</i>)-diazeniumdiolates from two bacterial species suggests stereospecific biosynthesis and transduction of these signals. Our findings set the stage for discovering diazeniumdiolate signals from other bacteria.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1029-1037"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Protein Degradation: From Basic Science to Therapeutic Applications.","authors":"Rongfeng Zhu, Xiaoyu Tang, Heng Zhang","doi":"10.1021/acschembio.5c00067","DOIUrl":"10.1021/acschembio.5c00067","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) is a groundbreaking approach in molecular therapeutics, enabling the selective elimination of specific proteins by leveraging the cell's own degradation machinery. In November 2024, the SMART Symposium titled \"<i>Targeted Protein Degradation: from basic science to therapeutic applications</i>\" offered a comprehensive communication on the cutting-edge chemical strategies and emerging clinical applications in this rapidly advancing field.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"979-982"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Rapaglutin E as an Isoform-Specific Inhibitor of Glucose Transporter 1.","authors":"Marnie Kotlyar, Zufeng Guo, A V Subba Rao, Hanjing Peng, Jingxin Wang, Zhongnan Ma, Cordelia Schiene-Fischer, Gunter Fischer, Jun O Liu","doi":"10.1021/acschembio.5c00152","DOIUrl":"10.1021/acschembio.5c00152","url":null,"abstract":"<p><p>Natural products rapamycin and FK506 are macrocyclic compounds with therapeutic benefits whose unique scaffold inspired the generation and exploration of hybrid macrocycle rapafucins. From this library, a potent inhibitor of the facilitative glucose transporter (GLUT), rapaglutin A (RgA), was previously identified. RgA is a pan-GLUT inhibitor of Class I isoforms GLUT1, GLUT3, and GLUT4. Herein, we report the discovery of rapaglutin E (RgE). Unlike RgA, RgE is highly specific for GLUT1. Further characterization revealed that RgE and RgA likely bound to distinct sites on GLUT1 despite their shared FKBP-binding domain, suggesting that the distinct effector domains of RgE and RgA play key roles in the recognition of GLUTs.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1004-1009"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Small-Molecule Activator of Patient-Derived GPX4 Variant.","authors":"Hengrui Liu, Farhad Forouhar, Russell Saneto, Brent R Stockwell","doi":"10.1021/acschembio.5c00158","DOIUrl":"10.1021/acschembio.5c00158","url":null,"abstract":"<p><p>Glutathione peroxidase 4 (GPX4) is distinguished from other members of the GPX family as being the enzyme capable of reducing phospholipid hydroperoxides within cellular membranes and therefore protecting cells from ferroptosis, a form of iron-driven cell death involving lipid peroxidation. We previously identified a homozygous point mutation in the <i>GPX4</i> gene, resulting in an R152H coding mutation and a substantial loss of GPX4 enzymatic activity, in patients with Sedaghatian-type spondylometaphyseal dysplasia (SSMD), an ultrarare progressive disorder. To explore whether selective binding and correction of the loss of enzyme activity observed with this variant is possible, we screened 2.8 billion compounds in a DNA-encoded chemical library and identified compounds with remarkably selective binding affinities with the R152H variant (GPX4^R152H) over wild-type (GPX4^WT). Our structural optimization of these compounds led to the identification of analogues with improved potency for R152H GPX4. The most promising compounds selectively restored the enzyme activity of GPX4^R152H and specifically increased the viability of fibroblast and lymphoblast cells developed from an SSMD patient with the homozygous R152H variation but not control cells from a healthy parent or HEK293T cells undergoing ferroptosis induced by a wild-type GPX4 inhibitor. This approach represents a low-cost, high-throughput, and generalizable approach to identify targeted small-molecule therapeutics for missense variants, which features the potential to be broadly applied to diseases that bear point mutations on crucial proteins, including cancers.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1107-1122"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Selective Pharmacologic IRE1/XBP1s Activator with Enhanced Tissue Exposure.","authors":"Jie Sun, Kyunga Lee, Sergei Kutseikin, Adrian Guerrero, Bibiana Rius, Aparajita Madhavan, Chavin Buasakdi, Ka-Neng Cheong, Priyadarshini Chatterjee, Dorian A Rosen, Leonard Yoon, Maziar S Ardejani, Alejandra Mendoza, Jessica D Rosarda, Enrique Saez, Jeffery W Kelly, R Luke Wiseman","doi":"10.1021/acschembio.4c00867","DOIUrl":"10.1021/acschembio.4c00867","url":null,"abstract":"<p><p>Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) has emerged as a promising strategy to mitigate etiologically diverse diseases. Despite this promise, few compounds are available to selectively activate IRE1/XBP1s signaling to probe the biologic and therapeutic implications of this pathway in human disease. Recently, we identified the compound IXA4 as a highly selective activator of protective IRE1/XBP1s signaling. While IXA4 has proven useful for increasing IRE1/XBP1s signaling in cultured cells and mouse liver, the utility of this compound is restricted by its limited activity in other tissues. To broaden our ability to pharmacologically interrogate the impact of IRE1/XBP1s signaling <i>in vivo</i>, we sought to identify IRE1/XBP1s activators with greater tissue activity than IXA4. We reanalyzed 'hits' from the high throughput screen used to identify IXA4, selecting compounds from structural classes not previously pursued. We then performed global RNAseq to confirm that these compounds showed transcriptome-wide selectivity for IRE1/XBP1s activation. Functional profiling revealed compound IXA62 as a selective IRE1/XBP1s activator that reduced Aβ secretion from CHO^7PA2 cells and enhanced glucose-stimulated insulin secretion from rat insulinoma cells, mimicking the effects of IXA4 in these assays. IXA62 robustly and selectively activated IRE1/XBP1s signaling in the liver of mice dosed compound intraperitoneally or orally. In treated mice, IXA62 showed broader tissue activity, relative to IXA4, inducing expression of IRE1/XBP1s target genes in additional tissues such as kidney and lung. Collectively, our results designate IXA62 as a selective IRE1/XBP1s signaling activating compound with enhanced tissue activity, which increases our ability to pharmacologically probe the biologic significance and potential therapeutic utility of enhancing adaptive IRE1/XBP1s signaling <i>in vivo</i>.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"993-1003"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation.","authors":"Thi Hong Van Nguyen, Francois Ferron, Kazuma Murakami","doi":"10.1021/acschembio.5c00153","DOIUrl":"10.1021/acschembio.5c00153","url":null,"abstract":"<p><p>Human coronaviruses (HCoVs) include seven species: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. The last three, classified as <i>Betacoronaviruses</i>, are highly transmissible and have caused severe pandemics. HCoV infections primarily affect the respiratory system, leading to symptoms such as dry cough, fever, and breath shortness, which can progress to acute respiratory failure and death. Beyond respiratory effects, increasing evidence links HCoVs to neurological dysfunction. However, distinguishing direct neural complications from preexisting disorders, particularly in the elderly, remains challenging. This study examines the association between HCoVs and neurodegenerative diseases like Alzheimer disease, Parkinson disease, Lewy body dementia, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. It also presents the long-term neurological effects of HCoV infections and their differential impact across age groups and sexes. A key aspect of this study is the investigation of the sequence and structural similarities between amyloidogenic and HCoV spike proteins, which can provide insights into potential neuropathomechanisms.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"983-992"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}