European Journal of Medicinal Chemistry最新文献

{"title":"Synthesis and evaluation of new 5-(1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole derivatives and their application as OXPHOS inhibitors","authors":"Longcai Cao ,&nbsp;Han Yao ,&nbsp;Puzhuang Hou ,&nbsp;Yuanyuan Ren ,&nbsp;Haitao Zhi ,&nbsp;Xian Jia ,&nbsp;Xingshu Li","doi":"10.1016/j.ejmech.2025.117903","DOIUrl":"10.1016/j.ejmech.2025.117903","url":null,"abstract":"<div><div>Twenty new 5-(1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole derivatives were synthesized and evaluated as OXPHOS inhibitors against cancers. The anti-proliferation assay exhibited that most of the compounds possessed good to excellent inhibitory activity on PC9 non-small cell lung cancer cells and Bxpc-3 pancreatic cancer cells. Among them, the optimal compound <strong>28c</strong>, provided 0.0123 μM of IC₅₀ value on PC9 cells, 0.25 μM and 0.0173 μM of the IC₅₀ values against Bxpc-3 cells in glucose and galactose medium, respectively. In PC9 xenograft nude mice, TGI of <strong>28c</strong> is 74.4 % compared with 44.16 % of the reference <strong>IACS-010759</strong> when oral administration at dosage of 7.5 mg/kg. Mechanism research showed that <strong>28c</strong> can bind with respiratory chain complex I, modulate the levels of NADH, NAD⁺ et al. in PC9 cells, activate cellular ROS and down regulate NRF2 and cause DNA damage in tumor cells.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117903"},"PeriodicalIF":6.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational optimization of D3R/GSK-3β dual target-directed ligands as potential treatment for bipolar disorder: Design, synthesis, X-ray crystallography, molecular dynamics simulations, in vitro ADME, and in vivo pharmacokinetic studies","authors":"R.M.C. Di Martino ,&nbsp;D. Russo ,&nbsp;I. Penna ,&nbsp;S. Demuro ,&nbsp;A. Dalle Vedove ,&nbsp;R. Spagnuolo ,&nbsp;G. Ottonello ,&nbsp;S.M. Bertozzi ,&nbsp;M. Summa ,&nbsp;J. Desantis ,&nbsp;A. Valeri ,&nbsp;L. Pruccoli ,&nbsp;S.K. Tripathi ,&nbsp;A. Tarozzi ,&nbsp;P. Storici ,&nbsp;S. Girotto ,&nbsp;R. Bertorelli ,&nbsp;A. Armirotti ,&nbsp;G. Cruciani ,&nbsp;T. Bandiera ,&nbsp;G. Bottegoni","doi":"10.1016/j.ejmech.2025.117899","DOIUrl":"10.1016/j.ejmech.2025.117899","url":null,"abstract":"<div><div>Bipolar disorder is a complex neuropsychiatric condition with a significant unmet medical need, as current treatments lack disease-modifying properties and multimodal therapeutic effects. To overcome the limitations of single-target drugs, we designed dual-target ligands that combine partial agonism at the dopamine D3 receptor (D3R) with inhibition of glycogen synthase kinase-3β (GSK-3β). We previously identified ARN24161 (<strong>1</strong>) as a promising prototype, demonstrating partial agonism at D3R (EC₅₀ = 10.1 nM, % Eff. = 26.3) and GSK-3β inhibition (IC₅₀ = 561 nM). However, its drug-like properties remained suboptimal. To optimize this compound, we initiated a multidisciplinary refinement campaign, leveraging computational modeling and crystallographic data to fine-tune the balance between D3R and GSK-3β activity, reduce P-glycoprotein (P-gp) affinity, and improve the pharmacokinetic profile. This effort led to the identification of ARN25297 (<strong>5</strong>), a moderately balanced dual-target ligand that exhibits partial agonism at D3R (EC₅₀ = 13.1 nM, % Eff. = 17.1) and potent GSK-3β inhibition (IC₅₀ = 47.0 nM). Notably, ARN25657 (<strong>16</strong>) emerged as the most well-balanced candidate, demonstrating enhanced D3R partial agonism (EC₅₀ = 15.2 nM, % Eff. = 37.7) alongside strong GSK-3β inhibition (IC₅₀ = 19.3 nM). Compound <strong>16</strong> also exhibited the lowest P-gp inhibition and significant improvements in <em>in vitro</em> ADME properties compared to prototype <strong>1</strong>, while maintaining a balanced dual target profile. Although the PK profile of <strong>16</strong> remained comparable to that of prototype <strong>1</strong>, these findings lay the groundwork for further lead optimization and structural refinement, driving future <em>in vivo</em> proof-of-concept toward innovative therapeutic strategies for bipolar disorder and related neuropsychiatric conditions.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117899"},"PeriodicalIF":6.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of thiazolylcyanovinyl benzopyridone acids: Potential new generation antibacterial oxacins?","authors":"Qian-Yue Li ,&nbsp;Jing Zhang ,&nbsp;Le-Ping Dai ,&nbsp;Yi-Min Tan ,&nbsp;Wei-Wei Gao ,&nbsp;Yu Cheng ,&nbsp;Shao-Lin Zhang ,&nbsp;Cheng-He Zhou","doi":"10.1016/j.ejmech.2025.117901","DOIUrl":"10.1016/j.ejmech.2025.117901","url":null,"abstract":"<div><div>Here we reported a unique class of new structural thiazolylcyanovinyl benzopyridone acids (TBAs) with large potential to defeat the intractable global bacterial resistance. Some prepared TBAs demonstrated broad-spectrum antibacterial ability, especially ethyl TBA <strong>7b</strong> gave low MIC values of 0.25–0.5 μg/mL against all the tested bacteria, superior to norfloxacin and clinafloxacin. The highly active molecule <strong>7b</strong> not only showed imperceptible hemolysis, cytotoxicity, toxicity <em>in vivo</em> and drug resistance, but also effectually eradicated mature biofilm and rapidly sterilized <em>Klebsiella pneumonia</em>. Moreover, TBA <strong>7b</strong> exhibited high therapeutic efficacy in mouse model of wound infection. Mechanism explorations implied that TBA <strong>7b</strong> could intercalate into DNA and act on gyrase-DNA complex to block DNA supercoiling, trigger oxidative stress and inhibit lactate dehydrogenase to reduce metabolism, resulting in bacterial death and intracellular protein leakage. These results suggested that thiazolylcyanovinyl benzopyridone acids should hold the large promise for being exploited as next-generation antibacterial oxcains.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117901"},"PeriodicalIF":6.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel 1,2,3-triazole arylamide derivatives bearing dithiocarbamate moiety as dual inhibitors of tubulin and LSD1 with potent anticancer activity","authors":"Jian-Wei Ji ,&nbsp;Xiu-Juan Liu ,&nbsp;Ji Wu ,&nbsp;Zi-Yue Wang ,&nbsp;Jin-Bo Niu ,&nbsp;Jian Song ,&nbsp;Sai-Yang Zhang","doi":"10.1016/j.ejmech.2025.117879","DOIUrl":"10.1016/j.ejmech.2025.117879","url":null,"abstract":"<div><div>Targeted inhibition of tubulin polymerization or histone lysine-specific demethylase 1 (LSD1) is considered as a promising therapeutic strategy for cancer treatment. In this work, we reported the discovery of novel 1,2,3-triazole arylamide derivatives bearing dithiocarbamate moiety as dual tubulin polymerization and LSD1 inhibitors through the pharmacophore hybridization strategy, which were derived from the natural product <strong>Erianin</strong>, and evaluated their anticancer activity through <em>in vitro</em> assays. Among them, compound <strong>L-6</strong> was identified as a potent dual tubulin polymerization and LSD1 inhibitor with effective anticancer potency, which demonstrated broad-spectrum antiproliferative activity <em>in vitro</em> with IC₅₀ values below 100 nM against 13 cancer cell lines. Notably, it displayed remarkable inhibitory potency on MGC-803 (IC₅₀ = 33 nM) and HGC-27 (IC₅₀ = 49 nM) gastric cancer cells, which surpassed those of <strong>Erianin</strong> and the LSD1 inhibitor ORY-1001. Mechanism explorations demonstrated that compound <strong>L-6</strong> inhibited tubulin polymerization by targeting the colchicine binding site, thereby disrupting the microtubule network in gastric cancer cells. Additionally, it increased the methylation levels of H3K4me1/2 and H3K9me2/3 in a concentration-dependent manner, thus achieving epigenetic regulation. This dual mechanism involving microtubule depolymerization and epigenetic modulation enabled compound <strong>L-6</strong> to effectively suppress colony formation, induce G2/M phase arrest, and promote apoptosis in gastric cancer cells, as well as regulate the expression levels of cell cycle and apoptosis-related proteins. These findings suggested that compound <strong>L-6</strong>, as a novel dual-target inhibitor of tubulin and LSD1, exhibited potential for the treatment of gastric cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117879"},"PeriodicalIF":6.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel fluorescent amino-pyrazolines that detect and kill Mycobacterium tuberculosis","authors":"Yixin Cui ,&nbsp;Alice Lanne ,&nbsp;Sreenivas Avula ,&nbsp;Mariwan A. Hama Salih ,&nbsp;Xudan Peng ,&nbsp;Gavin Milne ,&nbsp;Geraint Jones ,&nbsp;John Ritchie ,&nbsp;Yiming Zhao ,&nbsp;Jon Frampton ,&nbsp;Micky Tortorella ,&nbsp;John S. Fossey ,&nbsp;Luke J. Alderwick ,&nbsp;Cleopatra Neagoie","doi":"10.1016/j.ejmech.2025.117889","DOIUrl":"10.1016/j.ejmech.2025.117889","url":null,"abstract":"<div><div>The emergence of multidrug-resistant <em>Mycobacterium tuberculosis</em> (MDR-TB) necessitates novel therapeutics with distinct mechanisms. Here, we report amino-pyrazoline derivatives as a new class of dual-functional antimycobacterial agents, integrating potent bactericidal activity with fluorescence-based bacterial imaging. Initial screening identified AP-07 as a promising hit compound (MIC₉₉: 40 μM against <em>Mycobacterium smegmatis</em>, 49 μM against <em>Mycobacterium bovis</em> BCG). Structure-based optimization led to the discovery of AP-02 and AP-05 as lead compounds, with enhanced activity (MIC₉₉: 13–16 μM against <em>M. smegmatis</em>; 20–25 μM against <em>M. bovis</em> BCG). Additionally, spontaneous resistance assays detected no resistant colonies, suggesting a low risk of resistance development. Mechanistic studies confirmed Ag85C as the primary molecular target, disrupting late-stage mycolic acid biosynthesis and impairing cell wall integrity. Notably, pyrazoline derivatives exhibit intrinsic fluorescence, selectively labeling intracellular mycobacteria while remaining non-toxic to host macrophages, enabling real-time bacterial imaging. This work establishes fluorescent amino-pyrazolines as a promising foundation for next-generation antitubercular agents, bridging diagnostics and therapy in tuberculosis drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117889"},"PeriodicalIF":6.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated structure- and ligand-based design, synthesis, and biological evaluation of potent thiazole-based multi-kinase PI3Kα and CDK2/8 inhibitors as anticancer agents","authors":"Abdalla R. Mohamed ,&nbsp;Ahmed M. El Kerdawy ,&nbsp;Mohamed R. Elnagar ,&nbsp;Mohamed H. Younis ,&nbsp;Abdullah Y.A. Alzahrani ,&nbsp;Sana B. Moussa ,&nbsp;Hanan H. Georgey ,&nbsp;Nagwa M. Abdel Gawad ,&nbsp;Eman R. Mohammed","doi":"10.1016/j.ejmech.2025.117902","DOIUrl":"10.1016/j.ejmech.2025.117902","url":null,"abstract":"<div><div>A small library of novel potential multi-kinase inhibitors was designed by integrating structure- and ligand-based design approaches through terms of hybridization and fragment-based design tools. The required key pharmacophoric features for the individual kinases' inhibition were fused to achieve the desired inhibitory activity against PI3Kα and CDK2, relying on our previously studied strategy of the structure- and ligand-based design approaches’ expansion. Thus, all the synthesized compounds were evaluated for their inhibitory activity against PI3Kα and CDK2/cyclin A2, in addition to CDK8/cyclin C. The newly synthesized compounds exhibited a promising activity at sub-micromolar concentrations toward the three enzymes, indicating the efficacy of the adopted strategies utilized in the current design. Additionally, all the new derivatives were evaluated for their antiproliferative activity at 10 μM against the full NCI-60 cell panel. Compounds <strong>3d</strong>, <strong>10b</strong> and <strong>11e</strong> revealed the highest mean growth inhibition (78.10, 67.41and 73.22 %, respectively). Compounds <strong>3d</strong>, <strong>10b</strong> and <strong>11e</strong> were selected for five-dose assay, where the results indicated higher activity against leukemia (MG-MID = 2.87, 2.65 and 2.74 μM, respectively), and breast cancer (MG-MID = 3.79, 3.29 and 3.34 μM, respectively). Compound <strong>10b</strong> displayed a potential activity against Leukemia SR cell line with GI₅₀ of 0.47 μM. <em>In vitro</em> normal Vero cell line cytotoxicity was conducted as well indicating non-significant cytotoxic effect. Modeling studies were achieved for the newly synthesized compounds within the crystal structures of PI3Kα and CDK2, along with CDK8, which augment the biological screening and insightfully validated the utilized design approach.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117902"},"PeriodicalIF":6.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of membrane-active cannabichromene derivatives as potent antibacterial agents","authors":"Bin Long ,&nbsp;Na Wang ,&nbsp;Zhangqun Hou ,&nbsp;Hefei Shi ,&nbsp;Yufei Che ,&nbsp;Yuchi Wang ,&nbsp;Ting Peng ,&nbsp;Yuqi Mao ,&nbsp;Tong Luo ,&nbsp;Ling Mei ,&nbsp;Hongbo Dong","doi":"10.1016/j.ejmech.2025.117888","DOIUrl":"10.1016/j.ejmech.2025.117888","url":null,"abstract":"<div><div>The increasing prevalence of multidrug-resistant (MDR) bacterial infections underscores the urgent need for novel antimicrobial agents with distinct mechanisms. In this study, we present the rational design and synthesis of cationic amphiphilic cannabichromene (CBC, <strong>1</strong>) derivatives that mimic antimicrobial peptides (AMPs). Structural optimization of CBC through the incorporation of quaternary ammonium cations improved hydrophilicity and expanded the antibacterial spectrum. Among the 35 derivatives, compound <strong>11F</strong> emerged as the lead candidate, exhibiting potent activity against Gram-positive (MIC = 0.25–0.5 μg/mL) and Gram-negative pathogens (MIC = 0.5–8 μg/mL), surpassing vancomycin and ceftazidime in efficacy. Mechanistic studies revealed that <strong>11F</strong> disrupts bacterial membranes through high-affinity binding to phosphatidylglycerol (PG), resulting in membrane permeabilization and cytoplasmic leakage. Molecular dynamics simulations supported its membrane-targeting mechanism, driven by amphiphilic insertion into lipid bilayers. The synergistic accumulation of reactive oxygen species (ROS) further amplified the bactericidal effects. Compound <strong>11F</strong> demonstrated low hemolysis and cytotoxicity, showing <em>in vivo</em> efficacy in a murine MRSA sepsis model (98.8 % bacterial reduction at 10 mg/kg) and displaying excellent safety. This study establishes compound <strong>11F</strong> as a promising membrane-active antibacterial agent with potential for translation into clinical use against MDR infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117888"},"PeriodicalIF":6.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orphan GPCRs regulate the metabolic liver diseases through mediating the crosstalk between the liver and immune cells: Mechanisms and therapeutics","authors":"Yining Lin ,&nbsp;Yibing Wang","doi":"10.1016/j.ejmech.2025.117906","DOIUrl":"10.1016/j.ejmech.2025.117906","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver condition with increasing prevalence and few therapeutic options. Inflammatory pathways elicited by intrahepatic cell-autonomous ways or infiltration of immune cells are tightly coordinated to drive the progression of MASLD. Besides the extensively studied intrahepatic inflammatory pathways, the novel genes that mediate immune cell-liver crosstalk greatly impact the severity of MASLD and liver fibrosis by migration of immune cells into the liver. Among the genes are orphan G protein-coupled receptors (GPCRs), which are previously understudied transmembrane receptors without validated ligands. Here we critically discuss the emerging dual functions of GPR65, GPR18 and GPR84 expressed in bone marrow-derived immune cells in the progression of MASLD. They orchestrate the immune cell-liver crosstalk and regulate certain stages in the progression of MASLD. Our analyses indicate that GPR65, GPR18 and GPR84 are validated new targets for treating MASLD. GPR65 antagonists, GPR18 and GPR84 agonists are promising lead compounds for ameliorating MASLD and liver fibrosis through biasedly regulating the GPCR-coupled downstream signaling. The mechanisms, advantages and limitation of the agonists and antagonists have been critically discussed. The emerging critical function of orphan GPCRs in regulating the immune cell-liver crosstalk deepens our understanding of the pathogenesis of MASLD and liver fibrosis. Moreover, the concepts of biased agonists and pepducins that mimic the intracellular loops of GPCRs provide new approaches to address the challenges in the selectivity of targeting orphan GPCR-mediated immune cell-liver crosstalk and the treatment of MASLD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117906"},"PeriodicalIF":6.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and evaluation of lactam and maleimide derivatives of 16-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide from Polyalthia longifolia as potential anticancer agents","authors":"Sushil Kumar ,&nbsp;Alka Raj Pandey ,&nbsp;Suriya Pratap Singh ,&nbsp;Abinash Swain ,&nbsp;Amol Chhatrapati Bisen ,&nbsp;Sristi Agrawal ,&nbsp;Shahid Parwez ,&nbsp;Durga Prasad Mishra ,&nbsp;Rabi Sankar Bhatta ,&nbsp;Mohammad Imran Siddiqi ,&nbsp;Dibyendu Banerjee ,&nbsp;Koneni V. Sashidhara","doi":"10.1016/j.ejmech.2025.117894","DOIUrl":"10.1016/j.ejmech.2025.117894","url":null,"abstract":"<div><div>Diterpenes are plant secondary metabolites with diverse bioactivities, yet their anticancer potential remains underexplored. Here, we report the design and synthesis of thirty-nine novel derivatives of clerodane diterpene <strong>1</strong>, isolated from <em>Polyalthia longifolia</em>, including twenty lactam and nineteen maleimide analogs.</div><div>All compounds were screened at 10 μM against colon (DLD-1, HCT116, HT-29) and breast (MCF-7, MDA-MB-231, 4T1) cancer cell lines. Compound <strong>5o</strong> emerged as the lead, demonstrating significant growth inhibition (&gt;70 %) in colon cancer cells. Subsequent IC₅₀ determinations across seven cancer types (colon, breast, lung, hepatic, ovarian, cervical, prostate) revealed highest selectivity for the 5-fluorouracil-resistant DLD-1 cell line.</div><div>Mechanistic studies showed that <strong>5o</strong> induces caspase-dependent apoptosis, triggers reactive oxygen species (ROS) generation, and causes DNA damage, leading to cell-cycle arrest. Importantly, <strong>5o</strong> exhibited minimal cytotoxicity toward normal human cell lines (HEK293, MCF10A) and effectively suppressed colony formation and migration in both 2D and 3D colon cancer models.</div><div>Metabolic stability assays in simulated gastric, intestinal, and plasma fluids confirmed that &gt;80 % of <strong>5o</strong> remains intact over 4 h, and pharmacokinetic profiling in mice showed a half-life of ∼3.0 h with favorable oral bioavailability. In a Balb/c colon cancer xenograft model, oral dosing of <strong>5o</strong> produced significant tumor growth inhibition without observable toxicity. Together, these data establish <strong>5o</strong> as a promising lead for the development of new oral therapies targeting colon cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117894"},"PeriodicalIF":6.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current insights and barriers in FGFR-mediated signaling in lung cancer","authors":"Xiaohong Liu ,&nbsp;Wuxuan Mei ,&nbsp;Yueru Yao ,&nbsp;Changchun Zeng","doi":"10.1016/j.ejmech.2025.117897","DOIUrl":"10.1016/j.ejmech.2025.117897","url":null,"abstract":"<div><div>Lung cancer remains a significant health challenge, with fibroblast growth factor receptor (FGFR) signaling emerging as a critical player in its pathogenesis. This review examines FGFR's roles in endothelial function, angiogenesis, immune modulation, epithelial-to-mesenchymal transition (EMT), and transdifferentiation in lung cancer. Moreover, FGFR signaling is implicated in resistance to receptor tyrosine kinase (RTK) tyrosine kinase inhibitors (TKIs), particularly those targeting EGFR, ALK, and MET, immune checkpoint inhibitors, and chemotherapies in lung cancer. Furthermore, therapeutic approaches targeting FGFR include multitarget TKIs and selective FGFR inhibitors, which have shown promise in individuals with FGFR alterations. The side effects of FGFR inhibitors in clinical settings and associated management strategies have also been outlined. Additionally, challenges in personalizing FGFR therapies include variable FGFR alterations, diagnostic hurdles, biomarker selection and validation, and trial design intricacies. This comprehensive overview underscores the necessity for innovative approaches to optimize FGFR-targeted therapies in lung cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117897"},"PeriodicalIF":6.0,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}