ACS Pharmacology and Translational Science最新文献

{"title":"","authors":"Susmita Roy, Mehnaz Parveen, Asis Bala* and Debjeet Sur*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.4c00661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144455342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NARI-29: A Novel Epalrestat Derivative Attenuates Pulmonary Fibrosis by Modulating the TGF-β/Smad Signaling","authors":"Sai Balaji Andugulapati*,&nbsp;Vaishnavi Kambhampati,&nbsp;Abhisheik Eedara,&nbsp;Jagadeesh Kumar Gangasani,&nbsp;Harish Kumar B and V.G.M. Naidu*,&nbsp;","doi":"10.1021/acsptsci.5c0000910.1021/acsptsci.5c00009","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00009https://doi.org/10.1021/acsptsci.5c00009","url":null,"abstract":"<p >Pulmonary fibrosis is a chronic and debilitating lung disease marked by excessive collagen and extracellular matrix accumulation, leading to lung scarring and impaired lung function. Though pirfenidone and nintedanib are approved drugs, their efficacy is suboptimal. The current study aims to examine the antifibrotic activity of a novel epalrestat (aldose reductase) analog (NARI-29) using <i>in vitro</i> and <i>in vivo</i> rat models. The TGF-β-induced differentiation model utilized LL29/DHLF cells, while the bleomycin (BLCN)-induced pulmonary fibrosis (intratracheal route) model in rats was employed to evaluate the antifibrotic effects of NARI-29 using various molecular biology, histopathology, and lung function techniques. In the <i>in vitro</i> model, results from RT-qPCR and immunocytochemistry analysis demonstrated that NARI-29 treatment (2.5, 5, and 10 μM) significantly attenuated the expression of fibrotic markers induced by TGF-β. In the <i>in vivo</i> model, NARI-29 treatment (3.75, 7.5, and 15 mg/kg) significantly improved body weight and survival rates compared to the BLCN induction group. Gene and protein analysis showed elevated fibrotic markers expression (α-SMA, collagen1α1, fibronectin and other fibrotic markers) in the BLCN induction group, whereas NARI-29 or PFD treatment significantly reduced the same. Histology revealed that NARI-29 mitigated BLCN-induced fibrotic tissue formation, alveolar wall thickening, and lung distortion in a dose-dependent manner. Furthermore, pulmonary functional analysis revealed that NARI-29 treatment significantly attenuated BLCN-induced increases in Newtonian resistance and elastance, while enhancing inspiratory capacity and quasi-static compliance in a dose-dependent manner. The mechanistic evaluation revealed that NARI-29 alleviated fibrosis by modulating TGF-β/Smad signaling in lung tissues, as corroborated by molecular docking studies. Overall, the results of the current study demonstrated that treatment with NARI-29 significantly improved pulmonary fibrosis and lung function, highlighting its potential as a therapeutic candidate for IPF.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1610–1626 1610–1626"},"PeriodicalIF":4.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Nicole A. Emmons,&nbsp;Jennifer M. Gibson,&nbsp;Matthew H. McDonough,&nbsp;Julian Gerson,&nbsp;Murat Kaan Erdal,&nbsp;Kaylyn Leung,&nbsp;Lisa C. Fetter,&nbsp;Kevin W. Plaxco* and Tod E. Kippin*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144455335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Sourav Pal,&nbsp;Quinlin M. Hanson,&nbsp;Sarah C. Ogden,&nbsp;Emily M. Lee,&nbsp;Natalia J. Martinez and Alexey V. Zakharov*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144455338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Reshmi Kumari,&nbsp; and ,&nbsp;Satarupa Banerjee*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.4c00681","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144362292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Daniel Carbajo,&nbsp;Yolanda Pérez,&nbsp;Gabriela F. Castelo,&nbsp;Eva Prats,&nbsp;Jordi Bujons and Ignacio Alfonso*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.4c00747","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144362293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Gaurav Paraskar,&nbsp;Sankha Bhattacharya* and Anitha Kuttiappan*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.4c00686","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144455337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights of a p53-Targeting Small Molecule","authors":"Ricardo J. F. Ferreira,&nbsp;Valentina Barcherini,&nbsp;Catarina Roma-Rodrigues,&nbsp;Miriama Sikorová,&nbsp;Lucília Saraiva,&nbsp;Ana P. Leandro,&nbsp;Pedro V. Baptista,&nbsp;Alexandra R. Fernandes,&nbsp;Alexandra M. M. Antunes* and Maria M. M. Santos*,&nbsp;","doi":"10.1021/acsptsci.5c0011010.1021/acsptsci.5c00110","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00110https://doi.org/10.1021/acsptsci.5c00110","url":null,"abstract":"<p >Restoring the p53 pathway, particularly by reactivating wild-type (wt) or mutant (mut) p53, is considered a promising approach for cancer treatment. Previously, we identified the tryptophanol-derived oxazoloisoindolinone family as a new scaffold for obtaining wt and mut p53 reactivators. Herein, we report a detailed study on the pharmacokinetic profile and the mechanism of action of <b>RVJB59</b>, an (<i>R</i>)-tryptophanol-derived oxazoloisoindolinone that exhibits six times higher activity and increased selectivity for HCT116 cells with p53 compared to our initial hit, <b>SLMP53–1</b>. <i>In vitro</i> metabolic degradation studies in human liver microsomes and rat liver S9 fractions, assessed by LC/HRMS/MS, showed that <b>RVJB59</b> is a low-clearance compound. The three main metabolites identified were synthesized, and their antiproliferative activity was evaluated against HCT116 colon cancer cells with and without p53, showing a loss of activity when compared to <b>RVJB59</b>. DSF studies showed that <b>RVJB59</b> enhances the thermostability of the wt and R273H p53 DNA-binding domain, with this mutant showing melting curves with two melting transitions, distinct from those obtained for the wild-type. The ability of <b>RVJB59</b> to undergo covalent binding via nucleophilic aromatic substitution was assessed by HRMS/MS, using glutathione and wt p53 as case studies. These assays showed low reactivity toward glutathione and remarkable selectivity toward Cys141 of wt p53. The effect of <b>RVJB59</b> was also evaluated in 3D spheroids of HCT116 cells and <i>in vivo</i> using chicken embryos, with <b>RVJB59</b> reducing 3D tumor spheroid growth and exhibiting antiangiogenic potential. This study provides additional evidence of the potential of <b>RVJB59</b> in activating p53.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1726–1740 1726–1740"},"PeriodicalIF":4.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights of a p53-Targeting Small Molecule.","authors":"Ricardo J F Ferreira, Valentina Barcherini, Catarina Roma-Rodrigues, Miriama Sikorová, Lucília Saraiva, Ana P Leandro, Pedro V Baptista, Alexandra R Fernandes, Alexandra M M Antunes, Maria M M Santos","doi":"10.1021/acsptsci.5c00110","DOIUrl":"10.1021/acsptsci.5c00110","url":null,"abstract":"<p><p>Restoring the p53 pathway, particularly by reactivating wild-type (wt) or mutant (mut) p53, is considered a promising approach for cancer treatment. Previously, we identified the tryptophanol-derived oxazoloisoindolinone family as a new scaffold for obtaining wt and mut p53 reactivators. Herein, we report a detailed study on the pharmacokinetic profile and the mechanism of action of <b>RVJB59</b>, an (<i>R</i>)-tryptophanol-derived oxazoloisoindolinone that exhibits six times higher activity and increased selectivity for HCT116 cells with p53 compared to our initial hit, <b>SLMP53-1</b>. <i>In vitro</i> metabolic degradation studies in human liver microsomes and rat liver S9 fractions, assessed by LC/HRMS/MS, showed that <b>RVJB59</b> is a low-clearance compound. The three main metabolites identified were synthesized, and their antiproliferative activity was evaluated against HCT116 colon cancer cells with and without p53, showing a loss of activity when compared to <b>RVJB59</b>. DSF studies showed that <b>RVJB59</b> enhances the thermostability of the wt and R273H p53 DNA-binding domain, with this mutant showing melting curves with two melting transitions, distinct from those obtained for the wild-type. The ability of <b>RVJB59</b> to undergo covalent binding via nucleophilic aromatic substitution was assessed by HRMS/MS, using glutathione and wt p53 as case studies. These assays showed low reactivity toward glutathione and remarkable selectivity toward Cys141 of wt p53. The effect of <b>RVJB59</b> was also evaluated in 3D spheroids of HCT116 cells and <i>in vivo</i> using chicken embryos, with <b>RVJB59</b> reducing 3D tumor spheroid growth and exhibiting antiangiogenic potential. This study provides additional evidence of the potential of <b>RVJB59</b> in activating p53.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1726-1740"},"PeriodicalIF":4.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Neutrophil-Mediated Inflammation: Identification of Pyrazolidinone Carboxamide Derivatives as Potent Selective Inhibitors of Formyl Peptide Receptor 1 (FPR1)-Activated Neutrophils","authors":"Mohammad Abdel-Halim*,&nbsp;Reem A. Wagdy,&nbsp;Mohamed Salah,&nbsp;Yi-Hsuan Wang,&nbsp;Tzu-Peng Cheng,&nbsp;Yao-Rong Lee,&nbsp;Yu-Cheng Chen,&nbsp;Yasmine M. Mandour,&nbsp;Ashraf H. Abadi,&nbsp;Matthias Engel and Tsong-Long Hwang*,&nbsp;","doi":"10.1021/acsptsci.4c0071510.1021/acsptsci.4c00715","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00715https://doi.org/10.1021/acsptsci.4c00715","url":null,"abstract":"<p >Neutrophils play a critical role in the innate immune response, but their overactivation can lead to chronic inflammation and tissue damage in conditions such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and sepsis. Formyl peptide receptor 1 (FPR1) is a key regulator of neutrophil activation, making it an attractive target for therapeutic intervention. In this study, an in-house screening revealed pyrazolidinone carboxamide derivatives as effective inhibitors of neutrophil activation, exhibiting no cytotoxic effects. Compounds <b>10</b>–<b>12</b> and <b>21</b> demonstrated selective inhibition of FPR1-induced neutrophil superoxide anion production and elastase release with submicromolar IC₅₀ values, while having no effect on the FPR2 pathway. On a structural level, electron-withdrawing groups on the thiazole ring within the amide side chain were found to be crucial for high potency. Binding assays confirmed that compounds <b>10</b>, <b>11</b> and <b>21</b> act as direct antagonists of FPR1. In the LPS-induced acute respiratory distress syndrom (ARDS) model in mice, compound <b>10</b> significantly reduced pulmonary inflammation, oxidative stress, and neutrophil elastase activity, while showing no signs of toxicity in the liver or kidneys at the tested doses, highlighting its protective effects. Furthermore, molecular docking and dynamic simulations provided insights into their binding poses, explaining their interactions with key residues within the FPR1 binding site. This study lays the foundation for optimizing this class of compounds as therapeutic agents for controlling neutrophil-mediated inflammation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1591–1609 1591–1609"},"PeriodicalIF":4.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}