RSC medicinal chemistry最新文献

{"title":"Design, synthesis, and structure-activity relationships of novel flavone derivatives as tankyrase inhibitors against colorectal cancer.","authors":"Haiping Yao, Zhu Wang, Nianyu Huang, Nengzhong Wang, Guoping Gan","doi":"10.1039/d6md00521g","DOIUrl":"https://doi.org/10.1039/d6md00521g","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a lethal malignancy driven by Wnt/β-catenin pathway hyperactivation. Tankyrase (TNKS) is a promising therapeutic target for CRC; however, existing inhibitors suffer from poor subtype selectivity and severe intestinal toxicity. Guided by structure-based drug design (SBDD), we developed a novel series of flavone-based TNKS inhibitors using 4'-hydroxyflavone, a plant-derived hit, as the structural scaffold. By systematically introducing diverse aliphatic amines and fluorine atoms onto the flavone B-ring, we designed and synthesized 37 derivatives. Structure-activity relationship (SAR) analysis revealed that bulky <i>para</i>-dialkylamides significantly improved binding affinity. Among the series, compound 19 showed the strongest TNKS1 inhibitory potency (IC₅₀ = 40.6 nM) and >250-fold selectivity over PARP-1. Compound 21 emerged as the optimized lead, effectively suppressing SW480 CRC cell proliferation (IC₅₀ = 6.7 μM) while maintaining a superior safety window (SI > 15) against normal NCM460 colonic epithelial cells. Mechanistically, compound 21 exerted its antitumor effects by significantly downregulating classic Wnt target genes (<i>AXIN2</i>, <i>c-Myc</i>), reversing the epithelial-mesenchymal transition (EMT), and irreversibly abolishing the long-term colony-forming capacity of CRC cells. In conclusion, compound 21 features a unique dual-pocket occupation mode and an outstanding efficacy-safety balance, providing a highly valuable structural template for developing next-generation, high-selectivity TNKS inhibitors for targeted CRC therapy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategic development of benzimidazole-derived glycosidase modulators for antihyperglycemic intervention: a comprehensive medicinal study integrating molecular docking, biological evaluation, <i>in vivo</i> validation and pharmacokinetic assessment.","authors":"Zanib Fiaz, Shoaib Khan, Tayyiaba Iqbal, Khurram Shoaib, Masi A Almalki, Faez Alotaibi, Khasan Kayumov, Souhir Abid, Majdi Abid, Sobhi M Gomha, Magdi E A Zaki","doi":"10.1039/d6md00575f","DOIUrl":"https://doi.org/10.1039/d6md00575f","url":null,"abstract":"<p><p>Current <i>in silico</i> drug discovery workflows largely rely on ligand-based screening and structure-based molecular docking to identify enzyme inhibitors, often overlooking dynamic biological contexts that influence drug efficacy and stability. Integrating multiscale computational modeling with experimental validation at early stages of lead identification can significantly improve predictive accuracy and reduce attrition rates. In this study, we applied an integrated computational-biological framework to identify benzimidazole-based thiophene-derived bis-Schiff base derivatives as potential antidiabetic agents targeting α-amylase and α-glucosidase. Lead compounds were prioritized through molecular docking, pharmacophore modeling, density functional theory (DFT) analysis, quantitative structure-activity relationship (QSAR) modeling, and molecular dynamics (MD) simulations to evaluate binding affinity, electronic features, and protein-ligand stability. The computational predictions were corroborated by <i>in vitro</i> enzyme inhibition assays, identifying compound 1 as the most potent inhibitor with superior activity compared to acarbose. Furthermore, <i>in vivo</i> wound-healing evaluation in rabbit models demonstrated enhanced tissue regeneration and accelerated healing, indicating biological relevance beyond enzymatic inhibition. <i>In silico</i> ADMET analysis predicted favorable pharmacokinetic and low-toxicity profiles for the lead compound. Although demonstrated for α-amylase and α-glucosidase inhibition, the proposed integrative framework is readily adaptable to other enzyme-driven therapeutic discovery pipelines.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13693544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Synthesis, antibacterial activity, and mechanistic characterization of novel 9-substituted berberine derivatives.","authors":"Jiaying Tong, Huamao Yang, Yeying He, Kejie Chen, Chaoyue Chen, Haoyi Han, Chenping Li","doi":"10.1039/d6md90033j","DOIUrl":"10.1039/d6md90033j","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1039/D5MD00825E.].</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":"5113-5114"},"PeriodicalIF":4.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On-DNA photochemical methods for expanding DNA-encoded library (DEL) chemical space.","authors":"Oliver J Corrigan, Sarah L Allinson, Jamie H Docherty","doi":"10.1039/d6md00764c","DOIUrl":"10.1039/d6md00764c","url":null,"abstract":"<p><p>DNA-encoded libraries (DELs) have become a mainstay of small-molecule discovery, enabling millions to billions of compounds to be screened in a single pooled affinity selection in which each small molecule is covalently linked to a unique DNA identifier. However, the chemistry available for their construction remains limited compared to conventional synthetic chemistry. On-DNA chemistry is constrained by the requirement for aqueous, dilute, and DNA-compatible conditions. Classical on-DNA reactions such as amide coupling, reductive amination, S_NAr and transition-metal cross-coupling have enabled reliable library synthesis, but they tend to favour planar, sp²-rich products. Photochemistry and photocatalysis have recently emerged as a powerful strategy to broaden this toolbox. Excited-state activation opens reaction pathways that are difficult or impossible to reach through conventional ground-state chemistry and can facilitate novel transformations towards the construction of more complex and sp³-rich scaffolds. This review surveys the field of on-DNA photochemistry, looking at different activation modes including photoredox single-electron transfer (SET), hydrogen-atom transfer (HAT), metallaphotoredox dual catalysis, electron donor-acceptor (EDA) complexes, energy-transfer (EnT) catalysis, and direct photolysis. Collectively, these methods have translated a broad range of useful transformations to be amenable to on-DNA synthesis and unlocked access to many medicinally valuable motifs.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism-based precision pharmacology of natural products for triple-negative breast cancer: translational opportunities for targeted therapeutics.","authors":"Hadir M Emara, Nageh K Allam","doi":"10.1039/d6md00590j","DOIUrl":"10.1039/d6md00590j","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains one of the most therapeutically challenging malignancies because of its pronounced molecular heterogeneity, aggressive progression, and frequent development of resistance to chemotherapy, targeted agents, and immunotherapy. Natural products offer a distinctive medicinal chemistry resource because their structurally diverse scaffolds can engage multiple oncogenic and immune-regulatory targets simultaneously; however, their potential in TNBC has largely been discussed in conventional descriptive reviews that catalog individual compounds and mechanisms without establishing a clinically actionable framework for their integration into precision therapy. This review addresses this gap by developing a mechanism-based precision pharmacology framework that connects natural-product chemical scaffolds, multitarget molecular mechanisms, TNBC vulnerabilities, and rational therapeutic combinations. We critically examine representative phytochemicals according to their ability to modulate clinically actionable pathways, including PI3K/AKT/mTOR, receptor tyrosine kinases (RTKs), poly(ADP-ribose) polymerase (PARP), programmed death-1/programmed death-ligand 1 (PD-1/PD-L1), androgen receptor (AR), and trophoblast cell surface antigen-2 (TROP-2), and relate these mechanisms to the molecular heterogeneity of TNBC. Particular emphasis is placed on how multitarget natural-product scaffolds may complement contemporary targeted therapies, antibody-drug conjugates, immunotherapies, and chemotherapy through pathway-directed and subtype-informed combinations. We further critically evaluate preclinical and clinical evidence to identify the major barriers limiting translation, including poor bioavailability, unfavorable pharmacokinetics, insufficient target engagement, suboptimal formulation, and the lack of biomarker-guided patient selection. Rather than viewing natural products as nonspecific complementary agents, we propose their repositioning as chemically defined multitarget pharmacological modulators whose therapeutic value can be optimized through structure-informed development, pharmacodynamic validation, molecular stratification, and rational combination design. Finally, we propose a precision pharmacology roadmap linking natural-product scaffold, molecular vulnerability, pharmacological mechanism, rational combination, pharmacodynamic biomarker, and biomarker-enriched clinical evaluation. By integrating medicinal chemistry, molecular pharmacology, and translational oncology, this review provides a distinct framework for advancing natural-product-derived therapeutics from broad anticancer activity toward mechanism-driven precision medicine in TNBC.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCA-mapping and machine learning identify multiple chemotypes with antiplasmodial, β-haematin and haemozoin formation inhibition activity.","authors":"Nicole Teixeira, Leah Amod, Clinton G L Veale, Timothy J Egan, Kathryn J Wicht","doi":"10.1039/d6md00582a","DOIUrl":"https://doi.org/10.1039/d6md00582a","url":null,"abstract":"<p><p>Inhibiting the formation of haemozoin remains a robust, non-genomic target for antiplasmodial drug discovery. While current efforts focus on multistage active compounds that are not pure haemozoin formation inhibitors, this class offers advantages including selectivity for <i>Plasmodium</i> and is associated with lowered resistance risks. With a view to developing cost-effective tools to streamline the discovery process, we developed a high-throughput virtual screening (HTVS) workflow integrating both ligand- and structure-based techniques. Here, we employed a principal component analysis (PCA) enrichment map to prioritise a commercial library for potential β-haematin (βH, the synthetic analogue of haemozoin) formation inhibitors. Compounds identified within the area of enrichment were subsequently evaluated using structure-based molecular docking to the βH crystal. A support vector machine (SVM) model was then applied to predict antiplasmodial activity, after which a diverse subset of the highest-ranking hits was validated through detergent-mediated βH formation inhibition and whole-cell <i>Plasmodium falciparum</i> (<i>Pf</i>) assays. Three frontrunner compounds (1, 2, and 14) were found to possess potent, sub-micromolar <i>Pf</i> inhibitory activity. Furthermore, compounds 1 and 2 were found to possess βH formation inhibitory activity, analogous to chloroquine, with cellular fractionation confirming haemozoin formation inhibition as a contributor to the whole-cell mechanism of action of compound 1. This accessible and efficient HTVS workflow provides a successful framework for identifying new chemotypes targeting the haem detoxification pathway and, through PCA modification, potentially other essential parasite processes.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design to neuroprotection: a blood brain barrier permeable selective HDAC3 inhibitor active against chemical and viral insults.","authors":"Darakhshan Begum, Sanjeev Regula, Suryansh Sengar, Sk Abdul Amin, Dharani Sen, Swati Biswas, Shovanlal Gayen, Vivek Sharma, Balaram Ghosh","doi":"10.1039/d6md00748a","DOIUrl":"10.1039/d6md00748a","url":null,"abstract":"<p><p>Neuronal loss in neurodegenerative diseases is mediated by oxidative stress, neuroinflammation, and epigenetic dysregulation, with histone deacetylase 3 (HDAC3) playing a central role in inflammatory signaling and neuronal damage. We synthesized 12 compounds and identified the lead compound 9c as a potent and selective HDAC3 inhibitor, with an IC₅₀ of 0.75 μM and at least 27-fold selectivity over other HDAC isoforms. Compound 9c exhibited significant neuroprotection against hydrogen peroxide (H₂O₂) induced oxidative stress in N2A cells and Japanese encephalitis virus (JEV)-induced cell death in SH-SY5Y cells. Further western blot analysis revealed upregulation of neuronal markers (CREB, BDNF, and synaptophysin) and increased histone acetylation (<i>Ac</i>-H3K9, <i>Ac</i>-H3K27, and <i>Ac</i>-H4K8). Treatment of SH-SY5Y cells with 9c during JEV infection reduces virus-induced caspase-3/7 activity. In addition, quantitative real-time PCR analysis revealed that 9c reduces the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) during JEV infection. Neurite outgrowth and neuronal differentiation assays demonstrated that 9c promotes neuronal growth and maturation. Pharmacokinetic studies showed substantial brain penetration of 9c, with a <i>C</i> _max of 1.84 μg mL^-1 at 1 h and <i>t</i> _1/2 of 4 h. Collectively, these findings suggest that selective HDAC3 inhibition by 9c confers neuroprotection, supporting its potential as a promising therapeutic candidate for neurodegenerative disorders.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging BET bromodomain and immune checkpoint inhibitors through generative bioorganic frameworks for next-generation cancer immunotherapy.","authors":"Mohamed K Diab, Asmaa S A Yassen, Sherif Ashraf Fahmy, Heba F Ashour, Mohamed S Nafie","doi":"10.1039/d6md00450d","DOIUrl":"10.1039/d6md00450d","url":null,"abstract":"<p><p>Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that couple chromatin acetylation to oncogenic and immune-regulatory gene transcription, making them attractive targets for combination with immune checkpoint inhibitors (ICIs) in precision oncology. This review synthesizes current mechanistic, medicinal-chemistry, and translational evidence on BET-ICI combination strategies. We describe how BET blockade reshapes tumor chromatin architecture, suppresses <i>PD-L1</i> expression, and enhances antigen presentation, thereby increasing tumor susceptibility to immune-mediated attack. We further summarize preclinical efficacy data for BET-ICI combinations, including systems-biology and agent-based computational models that predict substantially greater tumor-volume reduction with combination regimens relative to monotherapy in selected preclinical settings; however, early-phase clinical experience with these combinations remains limited and has not yet reproduced this magnitude of benefit. Beyond the mechanism, we review the medicinal chemistry underlying BET inhibitor design and the emerging landscape of BET-ICI hybrid and conjugate therapeutics, distinguishing combinations with direct experimental support from conceptual pairings that remain hypothesis-generating. Finally, we discuss how systems biology and generative, AI-guided molecular design may inform resistance-mechanism prediction, toxicity mitigation, and biomarker-guided, patient-specific compound selection. Collectively, this review outlines a framework for how the convergence of epigenetic reprogramming, immune modulation, and generative bioorganic chemistry could inform the rational design of next-generation BET-ICI combination therapeutics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13611828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Symmetry-guided fusion converts weak liver pyruvate kinase inhibitors into potent allosteric activators.","authors":"Leticia Monjas, Alexandra Rodriguez Rivero, Anders Foller Füchtbauer, Oscar Nilsson, Liliana Håversen, Aleksei Lulla, Paul Brear, Mikael Rutberg, Per-Olof Bergh, Jan Borén, Adil Mardinoglu, Marko Hyvönen, Morten Grøtli","doi":"10.1039/d6md00604c","DOIUrl":"10.1039/d6md00604c","url":null,"abstract":"<p><p>Structure-guided exploitation of symmetry within multimeric protein interfaces offers an opportunity to convert partial ligand-binding poses into higher-affinity modulators. Here, we report a class of symmetrical \"Z-shaped\" allosteric activators of human liver pyruvate kinase (PKL), generated by symmetry-guided fusion of binding poses identified in inhibitor-bound crystal structures. The resulting ligands span the inter-subunit pocket at the tetrameric dimer-dimer interface and display substantially enhanced activity, with several analogues showing nanomolar activation potency. In HepG2 PKM2-knockout cells, the compounds increased PKL activity, maximal mitochondrial respiratory capacity and glycolytic proton efflux without altering PKL expression, Ser113 phosphorylation-dependent localisation, cell proliferation or triglyceride accumulation under the conditions examined. These findings establish symmetry-guided ligand fusion as a productive design strategy in this PKL system and provide structurally defined chemical tools for investigating the metabolic consequences of direct PKL activation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13667364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous exploitation of phaeanthine - a bisbenzylisoquinoline alkaloid for dual anti-metastatic and anti-angiogenic potential by disruption of Akt/NF-κB/MMP regulatory pathways.","authors":"Alisha Valsan, Vishnu Priya Murali, Murugan Thulasi Meenu, Anuja Gracy Joseph, Kokkuvayil Vasu Radhakrishnan, Daisy R Sherin, Kaustabh Kumar Maiti","doi":"10.1039/d6md00545d","DOIUrl":"10.1039/d6md00545d","url":null,"abstract":"<p><p>Metastasis and angiogenesis are critical drivers of cancer progression, contributing to tumor aggressiveness and therapeutic resistance. Phaeanthine (PHA), a bisbenzylisoquinoline alkaloid isolated from <i>Cyclea peltata</i>, has previously demonstrated anticancer activity by inhibiting Akt signaling. The present study investigated the anti-metastatic and anti-angiogenic potential of PHA in triple-negative breast cancer (TNBC) and analysed the molecular changes associated with its activity using experimental and computational approaches. Anti-metastatic activity was evaluated in MDA-MB-231 cells using wound-healing, adhesion, and transwell invasion assays, followed by Western blot analysis of key regulatory proteins. Anti-angiogenic effects were assessed in EA.hy926 endothelial cells using tube formation assays and VEGFR2 immunofluorescence analysis. Molecular docking and molecular dynamics (MD) simulations were performed to investigate potential molecular interactions. PHA significantly inhibited the migration, adhesion, and invasion of MDA-MB-231 cells at sub-micromolar concentrations and induced apoptosis. It suppressed the expression of metastasis-associated proteins, including MMP-2, MMP-9, integrins, Akt, NF-κB, and HIF-1α, while reversing epithelial-mesenchymal transition, as evidenced by reduced N-cadherin and vimentin expression. In EA.hy926 cells, PHA markedly inhibited tube formation at 2 μM and downregulated VEGFR2 expression. <i>In silico</i> studies revealed favourable binding affinities (<-6.0 kcal mol^-1) toward multiple metastatic and angiogenic targets. Subsequently, MD simulations provided computational support for potential interactions of PHA with MMP-2 and MMP-9, consistent with their pronounced downregulation observed experimentally. Collectively, these findings indicate the dual anti-metastatic and anti-angiogenic effects of PHA through coordinated modulation of Akt/NF-κB/HIF-1α/MMP-associated proteins, extracellular-matrix remodeling and angiogenesis. This study provides the first evidence of the activity of PHA against TNBC and its anti-angiogenic potential, supporting further investigation of PHA as a potential lead phytochemical against TNBC-associated metastatic and angiogenic processes.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13609873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}