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,&nbsp;Jiangyan Cao,&nbsp;Ting Wu,&nbsp;Chenliang Shi,&nbsp;Junjie Wang,&nbsp;Beilei Wang,&nbsp;Ziping Qi,&nbsp;Hong Wu,&nbsp;Yun Wu,&nbsp;Aoli Wang,&nbsp;Jing Liu,&nbsp;Wenchao Wang* and Qingsong Liu*,&nbsp;","doi":"10.1021/acschembio.4c0087510.1021/acschembio.4c00875","DOIUrl":"https://doi.org/10.1021/acschembio.4c00875https://doi.org/10.1021/acschembio.4c00875","url":null,"abstract":"<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 &gt; 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":"20 6","pages":"1181–1194 1181–1194"},"PeriodicalIF":3.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320566","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,&nbsp;Ananya Majumdar,&nbsp;Netzahualcóyotl Arroyo-Currás and Caren L. Freel Meyers*,&nbsp;","doi":"10.1021/acschembio.5c0002510.1021/acschembio.5c00025","DOIUrl":"https://doi.org/10.1021/acschembio.5c00025https://doi.org/10.1021/acschembio.5c00025","url":null,"abstract":"<p >Pathogenic bacteria must swiftly adapt to dynamic infection environments in order to survive and colonize in the host. 1-Deoxy-<span>d</span>-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 <span>d</span>-glyceraldehyde-3-phosphate (<span>d</span>-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. <span>d</span>-GAP binding ostensibly disrupts this network to activate LThDP for decarboxylation. Our lab previously reported trihydroxybenzaldoxime inhibitors which are competitive with respect to <span>d</span>-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":"20 6","pages":"1195–1211 1195–1211"},"PeriodicalIF":3.5,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320564","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/cbv020i005_1935668","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144390554","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":"","authors":"Emily Micheloni,&nbsp;Samantha S. Watson,&nbsp;Penny J. Beuning* and Mary Jo Ondrechen*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144390564","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":"Structural Insights into Spare-Tire DNA G-Quadruplex from the Human VEGF Promoter","authors":"Ines Burkhart,&nbsp;Vivien Rose McKenney,&nbsp;Julia Wirmer-Bartoschek,&nbsp;J. Tassilo Grün,&nbsp;Alexander Heckel and Harald Schwalbe*,&nbsp;","doi":"10.1021/acschembio.5c0022610.1021/acschembio.5c00226","DOIUrl":"https://doi.org/10.1021/acschembio.5c00226https://doi.org/10.1021/acschembio.5c00226","url":null,"abstract":"<p >The vascular endothelial growth factor (<i>VEGF</i>) promoter region, which is involved in cancer progression, contains guanine-rich sequences capable of forming G-quadruplex (G4) structures. G4s play a critical role in transcriptional regulation and genomic stability and exhibit high structural polymorphism. The major <i>VEGF</i> G4 adopts a parallel topology involving the first four of five G-tracts (<i>VEGF</i>1234), while a potential “spare-tire” mechanism suggests the formation of <i>VEGF</i>1245 in response to oxidative damage. Here, we characterize this alternative G4 (<i>VEGF</i>1245), formed by excluding the third G-tract, using circular dichroism and nuclear magnetic resonance spectroscopy. Structural analysis reveals that <i>VEGF</i>1245 folds in a hybrid conformation. Different from the other five tracts containing G4s, for which various strand topologies can rapidly interconvert, <i>VEGF</i>1245 remains thermodynamically metastable and does not refold spontaneously into <i>VEGF</i>1234 at physiological temperatures. Further trapping of the <i>VEGF</i>1245 conformation by a photolabile protecting group and its in situ release documents that the transition to <i>VEGF</i>1234 requires elevated temperatures, implicating kinetic barriers in the refolding process and the delineation of <i>VEGF</i>1245 as a prominent metastable conformation. Our findings provide new insights into transcriptional regulation and DNA repair for cancer-related <i>VEGF</i>-G4.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1417–1425 1417–1425"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschembio.5c00226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320559","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":"","authors":"Jie Sun,&nbsp;Kyunga Lee,&nbsp;Sergei Kutseikin,&nbsp;Adrian Guerrero,&nbsp;Bibiana Rius,&nbsp;Aparajita Madhavan,&nbsp;Chavin Buasakdi,&nbsp;Ka-Neng Cheong,&nbsp;Priyadarshini Chatterjee,&nbsp;Dorian A. Rosen,&nbsp;Leonard Yoon,&nbsp;Maziar S. Ardejani,&nbsp;Alejandra Mendoza,&nbsp;Jessica D. Rosarda,&nbsp;Enrique Saez*,&nbsp;Jeffery W. Kelly* and R. Luke Wiseman*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.4c00867","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144361594","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":"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":"","authors":"Drake M. Crawford,&nbsp;Jack C. Roche,&nbsp;Qiang Guo,&nbsp;Christopher Brache and Bo Li*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.4c00837","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144390555","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}