European Journal of Medicinal Chemistry最新文献

{"title":"Discovery, structural modification and structure-activity relationship study of Echinulin derivatives as tyrosyl-DNA phosphodiesterase 1 inhibitors and their potential antitumor activity","authors":"Chuan-Sheng Yao, Jiaqi Zhu, Xiang Gao, Ao Chen, Yue-Wen Li, Wen-Ya Liu, Li-Shuang Guo, Yong-Chun Wu, Cui-Xian Zhang, Xi-Xin He, Lin-Kun An","doi":"10.1016/j.ejmech.2025.118040","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118040","url":null,"abstract":"Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme and a potential antitumor target. Inhibiting TDP1 can potentiate the efficacy of both chemotherapy and radiotherapy. Herein, we report the discovery of the natural product Echinulin as a novel TDP1 inhibitor (IC₅₀ = 5.6 μM). The structural modification of Echinulin gave fifty-one derivatives. The evaluation of TDP1 inhibition indicated that eight derivatives <strong>20</strong>, <strong>25</strong>, <strong>26</strong>, <strong>27</strong>, <strong>33</strong>, <strong>64</strong>, <strong>66</strong>, and <strong>67</strong> showed higher TDP1 inhibitory activity than Echinulin. <strong>33</strong> exhibited the highest TDP1 potency with an IC₅₀ value of 0.90 μM, and a strong synergistic effect with camptothecin in human skin melanoma SK-Mel-2 cells, but not in three cancer cells A549, HCT-116, MCF-7, and non-cancerous Ges-1 cells. Structure-activity relationship (SAR) and the hypothetical binding mode of <strong>33</strong> with TDP1 protein were also analyzed. These results highlight that the Echinulin scaffold is a novel chemotype for the development of TDP1 inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786944","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":"Novel β-carboline derivatives show promise as dual-target inhibitors of DNA and TOP2A for the treatment of triple negative breast cancer","authors":"Xiaoyu Xu, Xiangrong Lu, Xiao Liu, Yong Ling, Yumin Yang, Aiqin Jiang","doi":"10.1016/j.ejmech.2025.118041","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118041","url":null,"abstract":"Breast cancer is a leading cause of death among women globally, with triple-negative breast cancer (TNBC) being the most aggressive subtype. To develop effective and safe chemotherapeutic drugs, we identified TOP2A as a potential target due to its differential expression between breast cancer and normal tissues. By targeting hydrogen bond-van der Waals sites, we discovered three active amino acid sites in TOP2A (E461, D463, and D543) and designed a β-carboline derivative, DM1, targeting DNA and TOP2A using a molecular generation model, local docking, and optimization. Molecular dynamics simulations showed that DM1 binds effectively to DNA and TOP2A, with its amide linker co-anchoring E461 and D543 alongside Mg²⁺, while the β-carboline ring interacts with DNA and stabilizes the connection with D463. This binding disrupts Mg²⁺-mediated ATP stabilization and blocks DNA reconnection. DM1 shows strong antiproliferative activity against 4T1 cells (IC₅₀ = 1.12 ± 0.13 μM), outperforming etoposide (IC₅₀ = 9.37 ± 0.52 μM), and inhibits cell migration. Further experiments demonstrated that DM1 selectively binds to TOP2A, not TOP2B, induces DNA damage, and increases reactive oxygen species (ROS) in TNBC cells. Proteomics analysis confirmed that DM1's mechanism involves nucleosomes, replication forks, and heterochromatin related to the two targets. In a 4T1 xenograft model, DM1 achieves a 71.50% tumor growth inhibition (TGI) at 20 mg/kg, compared to etoposide's 30.93% TGI at the same dose. DM1 interacts with DNA and TOP2A to form a stable DM1-TOP2A-DNA ternary complex. This blocks DNA's normal function, induces double-strand breaks, causes ROS accumulation, and triggers apoptosis, thereby inhibiting TNBC progression.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787302","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":"The first-in-class 1,3,5-triazine-derived dual 5-HT6R/FAAH modulators in search for potential drug against neurodegenerative diseases with cognitive impairment","authors":"Kinga Czarnota-Łydka, Katarzyna Kucwaj-Brysz, Barbara Mordyl, Monika Głuch-Lutwin, Tadeusz Karcz, Magdalena Jastrzębska-Więsek, Anna Partyka, Monika Dąbrowska, Grzegorz Satała, Sylwia Sudoł-Tałaj, Leonardo Brunetti, Modesto de Candia, Rosa Purgatorio, Marco Cerini, Luca Piemontese, Sabina Podlewska, Gniewomir Latacz, Małgorzata Starek, Anna Wesołowska, Antonio Carrieri, Jadwiga Handzlik","doi":"10.1016/j.ejmech.2025.118026","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118026","url":null,"abstract":"Due to complex etiology, a promising approach to find an effective therapy of Alzheimer's disease (AD) lies in the search for multitarget ligands. Within this study, we have identified novel 1,3,5-triazine derivatives that modulate either the serotonin 5-HT₆ receptor and the fatty acid amide hydrolase (FAAH) enzyme, also slightly inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) enzymes, thus representing pioneering multitarget approach to address key pathological mechanisms in AD. Among the synthesized compounds, the <em>m</em>-chlorobenzyl- <strong>7</strong> (5-HT₆R p<em>K</em>_<em>i</em> = 7.59) and the trimethoxybenzyl- <strong>23</strong> (5-HT₆R p<em>K</em>_<em>i</em> = 6.33) derivatives exhibited the most favorable multitarget action, with 5-HT₆R selectivity over other GPCR off-targets. Comprehensive molecular modeling provided insights into the compounds interactions with the molecular targets considered. <em>In vitro</em> evaluations revealed satisfactory metabolic stability and low risks of toxicity, including neurotoxicity. Notably, <strong>23</strong> demonstrated significant neuroprotective effects against Aβ_1-42-induced toxicity in hippocampal model (HT-22). Furthermore, in a Novel Object Recognition (NOR) test, both <strong>7</strong> and <strong>23</strong> ameliorated MK-801-induced memory deficits in rats. The results indicate the therapeutic potential for these first-in-class dual modulators of both, endocannabinoid system (FAAH) and serotonergic (5-HT₆R) neurotransmission, to address neurodegenerative diseases such as AD.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786943","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 bioactivity of newly potent pleuromutilin derivatives","authors":"Zhun Li,&nbsp;Danqian Ma,&nbsp;Chang Liu,&nbsp;Xianlong Qi,&nbsp;Zhe Qin,&nbsp;Yajun Yang,&nbsp;Jianyong Li","doi":"10.1016/j.ejmech.2025.118037","DOIUrl":"10.1016/j.ejmech.2025.118037","url":null,"abstract":"<div><div>The overuse of antibiotics has led to the progressively severe issue of bacterial drug resistance. As a result, a large number of antibiotics available on the market show a notably diminished effectiveness against drug-resistant bacteria. Thus, a series of dimethylcysteamine pleuromutilin derivatives were designed and synthesized. Both <em>in vitro</em> and <em>in vivo</em> tests were conducted to evaluate their activities against bacteria. Most derivatives exhibited potent antibacterial effects against Gram - positive bacteria, and their antibacterial activities were superior to those of tiamulin.</div><div>Derivative <strong>4g</strong> showed exceptional antibacterial activity, having MIC values as low as 0.016 μg/mL. Furthermore, compared to tiamulin, it exhibited a significantly longer post-antibiotic effect (PAE) and a slower rate of resistance development. The molecular docking results of derivative <strong>4g</strong> were excellent, and it effectively inhibited the expression of green fluorescent protein (GFP) in bacteria. Derivative <strong>4g</strong> exhibited extremely low cytotoxicity and had low oral acute toxicity, with an LD₅₀ exceeding 2000 mg/kg of body weight. Derivative <strong>4g</strong> demonstrated a more powerful therapeutic impact against MRSA infection compared to tiamulin and valnemulin. Considering these results, derivative <strong>4g</strong> stands out as an extremely promising compound, having significant potential for the future development of therapeutic uses.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 118037"},"PeriodicalIF":5.9,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772773","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 and synthesis of novel 4-aryl-2-benzoyl-imidazoles as colchicine binding site inhibitors","authors":"Najah Albadari ,&nbsp;Yang Xie ,&nbsp;Qinghui Wang ,&nbsp;Darcie J. Miller ,&nbsp;Judith Quadrozzi Gruntz ,&nbsp;Michael L. Oldham ,&nbsp;Hao Chen ,&nbsp;Dejian Ma ,&nbsp;Zhongzhi Wu ,&nbsp;Duane D. Miller ,&nbsp;Wei Li","doi":"10.1016/j.ejmech.2025.118021","DOIUrl":"10.1016/j.ejmech.2025.118021","url":null,"abstract":"<div><div>Highly potent tubulin inhibitors serve as critical payloads in several FDA-approved antibody-drug conjugates (ADCs). However, all these compounds are natural products with complex structures, which limit the ability to adjust their physicochemical properties for the optimal balance between payload release and ADC stability during systemic circulation, as well as efficient tumor penetration. Although taxanes are widely used in cancer therapy, they are unsuitable for ADCs due to insufficient potency and a high tendency to develop acquired drug resistance. Colchicine binding site inhibitors (CBSIs) are attractive alternatives, offering tunable properties and the potential to overcome multidrug resistance associated with the use of many existing tubulin inhibitors. However, most CBSIs lack sufficient potency for viable ADC applications.</div><div>In our pursuit of a highly potent CBSI suitable for ADC use, we identified a novel series of sabizabulin derivatives. These compounds were evaluated <em>in vitro</em> across four cancer cell lines, including one with high resistance to taxanes. Among them, compound <strong>11b</strong> emerged as the most promising one with IC₅₀ values ranging from 0.6 nM to 1.3 nM in cancer cells, entering the potency range as a potential ADC payload. Importantly, <strong>11b</strong> also effectively overcame taxane-associated drug resistance. Mechanistic studies confirmed that <strong>11b</strong> directly binds to the colchicine site on tubulin, as demonstrated by its high-resolution crystal structure in a complex with tubulin protein. <em>In vivo</em> efficacy studies using a taxane-resistant prostate cancer xenograft model (PC-3/TxR) revealed that <strong>11b</strong> significantly suppressed tumor growth, disrupted angiogenesis, and induced apoptosis. Together, these findings highlight <strong>11b</strong> as a highly potent CBSI with the capability of overcoming acquired drug resistance to taxanes, suggesting its strong potential as a next-generation ADC payload.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 118021"},"PeriodicalIF":5.9,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772775","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":"Examining the 2-aryl-5-nitrobenzofuran-based hydrazones for anti-breast (MCF-7) cancer activity, potential to induce cell cycle arrest and inhibit receptor tyrosine kinases (VEGFR-2 & EGFR)","authors":"Jackson K. Nkoana ,&nbsp;Garland K. More ,&nbsp;Ahmed A. Elhenawy ,&nbsp;Malose J. Mphahlele","doi":"10.1016/j.ejmech.2025.118018","DOIUrl":"10.1016/j.ejmech.2025.118018","url":null,"abstract":"<div><div>The development of small molecules capable of inhibiting multiple oncogenic pathways, such as those driven by the vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, represents a promising strategy in anticancer drug discovery. A strategically iodinated benzaldehyde precursor <strong>1</strong> was synthesized and condensed with phenylhydrazine derivatives to yield the iodophenol-hydrazones <strong>2a</strong> and <strong>2b</strong>. Subsequent Sonogashira coupling and cycloisomerization afforded novel benzofuran-hydrazone hybrids <strong>3a–k</strong> with diverse aryl substituents. Compounds <strong>2</strong> and <strong>3</strong> were screened for <em>in vitro</em> cytotoxicity against the MCF-7 breast cancer cell line and non-cancerous Vero cells. The mechanism of action was investigated through cell cycle analysis, annexin staining, enzymatic inhibition assays against VEGFR-2 and EGFR, including comprehensive <em>in silico</em> studies. Compound <strong>3k</strong> featuring a 4-(trifluoromethylphenyl)hydrazone arm and a 2-(3,5-dimethoxyphenyl) substituent emerged as the most potent cytotoxic agent against MCF-7 cells (IC₅₀ = 4.21 μM) with a favorable selectivity index (SI = 2.1). This compound induced cell cycle arrest at the G0/G1 phase. Apoptosis was assessed on compounds <strong>3c</strong> and <strong>3k</strong> using the Muse® Annexin V &amp; Dead Cell Kit on the MCF-7 cells. Treatment with <strong>3c</strong> showed 70.5 % and 28.1 % rise in early and late apoptosis, respectively. Derivative <strong>3k</strong>, on the other hand, resulted in a 76.2 % increase in early apoptosis. In enzymatic assays, compound <strong>2b</strong> showed strong VEGFR-2 inhibition (IC₅₀ = 2.86 μM), while several benzofuran hybrids, notably <strong>3j</strong> (IC₅₀ = 3.35 μM) and <strong>3k</strong> (IC₅₀ = 3.37 μM), also displayed potent activity. Compound <strong>3f</strong> was the most effective EGFR inhibitor (IC₅₀ = 5.29 μM). Several derivatives, including <strong>3k</strong>, demonstrated promising dual VEGFR-2 and EGFR inhibitory profiles. Molecular modelling rationalized these findings, highlighting key structure-activity relationships (SARs). The ADMET predictions indicated excellent drug-like properties, particularly for the non-Pgp substrate series. The finding successfully identified compound <strong>3k</strong> as a lead dual inhibitor of VEGFR-2 and EGFR with significant anticancer activity and selectivity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 118018"},"PeriodicalIF":5.9,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144767108","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":"Arginine vs tryptophan-based β-turn in the β-hairpin antimicrobial peptides: Superior antibacterial properties of the arginine-containing β-turn sequences","authors":"Beibei Li, Pengyi Yan, Yao Liu, Xu Ouyang, Qingyang Xu, Jingying Zhang, Zufang Ba, Jie Liu, Yu Wang, Tingting Yang, Xueting Liu, Zhongwei Yu, Bingqian Ren, Liru Yuan, Yuhuan Zhao, Chao Zhong, Hui Liu, Yun Zhang, Sanhu Gou, Jingman Ni","doi":"10.1016/j.ejmech.2025.118014","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118014","url":null,"abstract":"The antimicrobial activity and toxicity of <em>β</em>-hairpin antimicrobial peptides (AMPs) primarily depend on their intramolecular <em>β</em>-sheet structure, which is crucially affected by the <em>β</em>-turn sequence. To determine whether the tryptophan or arginine motifs in the <em>β</em>-turn of <em>β</em>-hairpin AMPs exhibit greater therapeutic efficacy, a library of <em>β</em>-hairpin AMPs was designed based on the simplified template: (WK)_nX_m(KW)_n-NH₂ (X = Trp or Arg; n = 1, 2, 3; m = 1, 2, 3). The results indicate that AMPs containing arginine motifs within the <em>β</em>-turn sequence exhibit superior antibacterial activity and enhanced therapeutic efficacy. Notably, peptide N3R2 with \"-RR-\" as the symmetry center displayed potent antimicrobial activity and low toxicity. The enantiomer of N3R2, named D-N3R2, was synthesized to enhance proteolytic stability. D-N3R2 exhibited even more potent antimicrobial activity than N3R2. Furthermore, we comprehensively investigated the efficacy and toxicity in vitro and in vivo, stability, SAR, and mechanism of action.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756419","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 design and synthesis of 6-(piperazin-1-yl)imidazo[1,2-b]pyridazine derivatives as dual FXR/PPARδ agonists for treatment of pulmonary fibrosis","authors":"Lingfeng Yue ,&nbsp;Nan Jiang ,&nbsp;Xue Fan,&nbsp;Sha Xu,&nbsp;Yuhang Ren,&nbsp;Hongrui Lei,&nbsp;Xin Zhai","doi":"10.1016/j.ejmech.2025.118013","DOIUrl":"10.1016/j.ejmech.2025.118013","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive multifactorial lung disorder characterized by excessive deposition of fibrotic connective tissue. The activation of farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor <em>δ</em> (PPAR<em>δ</em>) demonstrated therapeutic efficacy in reducing fibrotic pathology, respectively, suggesting that dual FXR/PPAR<em>δ</em> up-regulators may provide a prospective approach to address the polypharmacy dilemma in fibrotic diseases. Herein, the identification campaign of 6-(piperazin-1-yl)imidazo[1,2-<em>b</em>]pyridazine derivatives as FXR/PPAR<em>δ</em> dual agonists was described through hybridation of FXR agonist <strong>GW-4064</strong> and PPAR<em>δ</em> agonist <strong>GW-0742</strong>. The following exhaustive <em>in vitro</em> FXR and PPAR<em>δ</em> activation studies culminated in the optimization of compound <strong>10g</strong>, which displayed potent dual-target activities with an FXR agonistic EC₅₀ of 12.28 nM and 69 % PPAR<em>δ</em> activation at 100 nM. In a Bleomycin-induced murine <em>in vivo</em> pulmonary fibrosis model, <strong>10g</strong> (40 mg/kg, QD) significantly attenuated collagen deposition and reduced the expression of <em>α</em>-SMA in lung tissue. Taken together, these results shed new light on the discovery of novel FXR/PPAR<em>δ</em> agonists for the treatment of IPF.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 118013"},"PeriodicalIF":5.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748148","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":"Targeting the HGF/MET axis in cancer: therapeutic promise for natural compounds","authors":"Pouya Goleij ,&nbsp;Mohammad Mahdi Heidari ,&nbsp;Hossein Motevalli ,&nbsp;Sajad Abolfazli ,&nbsp;Mohammad Amin Khazeei Tabari ,&nbsp;Aryan Rezaee ,&nbsp;Danaé S Larsen ,&nbsp;Maria Daglia ,&nbsp;Michael Aschner ,&nbsp;Haroon Khan","doi":"10.1016/j.ejmech.2025.118027","DOIUrl":"10.1016/j.ejmech.2025.118027","url":null,"abstract":"<div><div>The hepatocyte growth factor (HGF)/MET signaling pathway plays a pivotal role in cancer progression, metastasis, and therapeutic resistance, making it an attractive target for anticancer therapies. HGF, a multifunctional cytokine, binds to the MET receptor, triggering downstream pathways such as PI3K/AKT, MAPK/ERK, and STAT3, which regulate cell proliferation, survival, and epithelial-mesenchymal transition (EMT). Dysregulation of this pathway—through mutations, amplifications, or overexpression—contributes to tumorigenesis, drug resistance, and poor prognosis in various cancers, including lung, breast, gastric, and hepatocellular carcinomas. This review explores the molecular mechanisms of HGF/MET in cancer, highlights the therapeutic potential of natural compounds, and discusses ongoing clinical trials targeting this pathway. Despite advances in targeted therapies, resistance to MET inhibitors remains a clinical challenge, necessitating alternative strategies. Natural compounds, including flavonoids, curcumin, ginger derivatives, epigallocatechin-3-gallate (EGCG), honokiol, metformin, and resveratrol, exhibit potent inhibitory effects on the HGF/MET axis. These phytochemicals modulate MET expression, disrupt downstream signaling, and reverse chemoresistance by targeting key oncogenic mechanisms such as EMT, cancer stem cell (CSC) maintenance, and tumor microenvironment interactions. For instance, flavonoids like apigenin and quercetin suppress MET-mediated invasion, while curcumin inhibits PI3K/AKT/mTOR signaling. EGCG and honokiol demonstrate synergistic effects with conventional therapies, overcoming resistance in non-small cell lung cancer (NSCLC) and renal cell carcinoma. By synthesizing preclinical and clinical findings, this work highlights the therapeutic potential of phytochemicals as adjunctive or alternative agents, offering innovative approaches to enhance the efficacy and outcomes of cancer treatments.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 118027"},"PeriodicalIF":5.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737477","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 structure-activity relationship study of novel GLP-1/GIP/GCG triple receptor agonists","authors":"Jinhua Zhang ,&nbsp;Hongjiang Xu ,&nbsp;Yuanzhen Dong ,&nbsp;Jun Feng ,&nbsp;Ruifang Li","doi":"10.1016/j.ejmech.2025.118024","DOIUrl":"10.1016/j.ejmech.2025.118024","url":null,"abstract":"<div><div>In this study, to achieve more effective blood sugar lowering and weight-loss effects, eight glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic peptide (GIP)/glucagon (GCG) triple receptor agonists were designed and synthesized. Their sixteen related conjugates were obtained through Cys alkylation and Lys esterification modifications with two fatty acid side chains, respectively. After chemical structure confirmation using high-resolution mass spectrometry and peptide mapping, in vitro and in vivo biological effects of TRA01-24 were assessed. The structure-activity relationship (SAR) data on the amino acids, fatty acids, linkers and biological effects in vitro and in vivo of TRA01-24 have been summarized. Furthermore, peptide-protein molecular docking elucidated the structural basis for the biased agonist activity of TRA22 at GLP-1R, characterized by strong GLP-1R activation but weak GCGR and GIPR activation. In conclusion, a lead compound with excellent efficacy in vitro and in vivo, TRA24, was screened, which had better in vivo efficacy than tirzepatide in both normal and db/db mice.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 118024"},"PeriodicalIF":5.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748150","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}