Drug Development Research最新文献

{"title":"Pyrimidine-Derived Scaffolds Targeting VEGFR-2, EGFR, and HER-2: Synthesis, Anticancer/Immunomodulatory Evaluation, and In Silico Analysis.","authors":"Naglaa M Ahmed, Mohamed S Gaballah, Belen Altava, Ahmed H Lotfallah","doi":"10.1002/ddr.70314","DOIUrl":"10.1002/ddr.70314","url":null,"abstract":"<p><p>Following the common structural features of VEGFR-2, EGFR, and HER-2 kinase inhibitors, two newly synthesized series of 3,4-dihydropyrimidine 2(1H)-(thio)ones-5-carboxamide (2a-l) and thiouracil-5-sulfonyl derivatives (4a-e) were evaluated for anti-proliferative activity against colorectal (HCT-116) and breast (MCF-7) cancer cell lines. Among the designed series, Compounds 2h and 2l were the most potent derivatives across both tumor models, exhibiting IC₅₀ values of 23.3 and 30.9 μM (HCT-116), respectively, and 31.5 and 39.2 μM (MCF-7), respectively, compared to sorafenib (IC₅₀ = 8.8 and 11.6 μM, respectively). Interestingly, 2h and 2l displayed a favorable safety profile toward the normal human cell line WI-38, with IC₅₀ > 200 μM comparable to sorafenib (IC₅₀ = 192 μM). In vitro enzymatic assays, 2h and 2l derivatives emerged as potent multi-kinase inhibitors targeting VEGFR-2, EGFR, and HER-2 with IC₅₀ = 0.20, 0.21, and 0.19 μM, respectively, and IC₅₀ = 0.67, 0.53, and 0.40 μM, respectively, hence circumventing cancer resistance mechanisms. The most potent Compound 2h prompted apoptosis and necrosis at % G0-G1 phase in HCT-116 via the activation of caspase-3 and 8, with significant downregulation of anti-apoptotic protein Bcl-2. Additionally, Compound 2h markedly suppressed immunomodulatory proteins TNF-α and IL-6 levels by 80.9% and 88.2%, respectively, in comparison to dexamethasone (82.7% and 93.2%, respectively), which attenuates tumor-promoting inflammation, disrupting pro-survival signaling pathways and metastasis. In silico ADMET, toxicity, and molecular docking studies were performed; notably, the docking simulations generated an interesting hypothesis for potential direct binding to Bcl-2, an effect distinct from the experimentally observed downstream downregulation of its expression. The present results pave the way for further developing of 2h candidate as a multi-tyrosine kinases inhibitor toward colon cancer cells.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70314"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling Key Genes Related to Fatty Acid Metabolism in Neuropathic Pain.","authors":"Ye Wang, Can Liu, Mingfang Wang, Yuefeng Wang, Yumei Zhou","doi":"10.1002/ddr.70309","DOIUrl":"10.1002/ddr.70309","url":null,"abstract":"<p><p>Neuropathic pain (NP), a chronic condition resulting from nerve injury or dysfunction, represents considerable therapeutic difficulties owing to its intricate and multifactorial pathophysiology. Recent studies indicate that dysregulated fatty acid metabolism (FAM) plays a pivotal role in the onset and persistence of NP. Nonetheless, the molecular mechanisms underpinning this association remain incompletely elucidated. This research aims to characterize the expression profiles of FAM-related genes in NP and explore their relationship with immune cell infiltration (ICI). Publicly available gene expression data sets (GSE24982 and GSE2884) were analyzed using bioinformatics approaches to identify differentially expressed genes (DEGs) related to FAM in NP. Differential expression analysis was performed using the limma package in R. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA), were carried out to elucidate relevant biological pathways. ICI was assessed using computational deconvolution methods. Overall, 116 FAM-related DEGs were identified in NP. Enrichment analyses highlighted key pathways such as FAM, arachidonic acid metabolism, and the PPAR signal transduction. Among these, Cyp3a2, Hadha, and Scp2 emerged as key genes potentially involved in NP pathogenesis, with Cyp3a2 exhibiting high mRNA levels in validated animal models. ICI analysis revealed significant correlations between the expression of these genes and various immune cell populations, including activated B cells and CD8⁺ T cells, indicating a strong inflammatory component in NP. Moreover, stratification by FAM scores demonstrated distinct gene expression and immune infiltration profiles between low- and high-risk groups. This study highlights the essential role of FAM in the molecular landscape of NP and identifies Cyp3a2, Hadha, and Scp2 as potential biomarkers or therapeutic targets. These findings advance our understanding of NP pathogenesis and offer insights into novel strategies for its management.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70309"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astragaloside IV Enhances Anti-PD-L1 Immunotherapy in Triple-Negative Breast Cancer by Activating the cGAS-STING Pathway.","authors":"Chuanchao Wei, Qing Zhang, Anwei Mao, Gaofeng Pan, Jiazhe Liu, Xinjuan Fan, Hongchang Li","doi":"10.1002/ddr.70311","DOIUrl":"10.1002/ddr.70311","url":null,"abstract":"<p><p>Astragaloside IV (AS-IV), a natural compound from traditional Chinese medicine, has demonstrated anti-tumor properties. This study aims to explore its potential to enhance anti-mPD-L1 immunotherapy in triple-negative breast cancer (TNBC) by modulating the tumor immune microenvironment. Flow cytometry and immunofluorescence staining analyses were employed to evaluate the influence of AS-IV on cell cycle distribution, apoptosis and DNA damage (phospho-γH2AX staining). The antitumor effects of AS-IV, anti-mPD-L1, or their combination were further investigated using a 4T1 murine breast cancer model. Immune cell infiltration within the tumor tissue was assessed by flow cytometry. AS-IV significantly triggered apoptosis, G0-G1 cell cycle arrest, as well as induced DNA damage and activation of the cGAS-STING pathway in MDA-MB-231 and 4T1 cells. Interestingly, AS-IV notably elevated PD-L1 levels both in two TNBC cells. In vivo experiments indicated that AS-IV treatment notably suppressed tumor growth and triggered tumor cell apoptosis. Meanwhile, AS-IV enhanced anti-tumor efficacy of anti-mPD-L1 on 4T1 murine model, as evidenced by increased infiltration of CD8⁺T cells and elevated secretion of IFN-β, CCL5, and CXCL10. AS-IV remodeled the tumor immune microenvironment and induced PD-L1 upregulation, thereby potentiating the efficacy of anti-mPD-L1 immunotherapy. These findings suggest that AS-IV may serve as a promising immunomodulatory adjuvant in cancer immunotherapy for TNBC.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70311"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-Function Lipid-Based Nanovector Strategy for Glioblastoma Immunotherapy: STING Activation and M1 Microglia Polarization.","authors":"Mohamed S Nafie, Mohamed Khaled Diab, Sherif Ashraf Fahmy","doi":"10.1002/ddr.70312","DOIUrl":"10.1002/ddr.70312","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains one of the most lethal brain malignancies because of its highly immunosuppressive tumor microenvironment and the limited penetration of therapeutics across the blood-brain barrier (BBB). Although recent studies have separately explored STING agonism, microglial reprogramming, and nanocarrier-based drug delivery, an integrated framework combining these strategies for GBM immunotherapy is still lacking. In this review, we present a new dual-function lipid-based nanovector (LNV) strategy that simultaneously activates the cGAS-STING pathway and induces tumor-associated microglia to repolarize toward the antitumor M1 phenotype. In contrast to previous reviews, which address them as individual approaches, herein we consolidate these into an integrated therapeutic paradigm and provide a rational design roadmap based on drug cargo selection, lipid isoform composition, BBB targeting, and thermo-/magnetically responsive release. We summarize how STING activation enhances type I interferon signaling, dendritic cell maturation, and cytotoxic T-cell priming, while M1-polarized microglia potentiate local inflammatory and phagocytic antitumor responses. In addition, we summarize the current nanocarrier platforms, preclinical evidence, and translational design considerations pertinent to this combinatorial approach. This review provides a conceptually integrated overview of the potential of dual-action lipid nanovectors to overcome clinically relevant immunological and delivery barriers in GBM, as well as future directions for next-generation nano-immunotherapies.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70312"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13161948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873722","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":"Exploring the Role of Novel N (4) Substituted 5,7-Dibromoisatin Thiosemicarbazones in Modulating PTOV1 Activity for Therapeutic Relevance in Breast Cancer.","authors":"Piyush Kumar, Upendra Chaudhary, Kuldeep Mahiya, Anshuman Chandra, Vijay Kumar Goel, Yuba Raj Pokharel, Paras Nath Yadav","doi":"10.1002/ddr.70306","DOIUrl":"10.1002/ddr.70306","url":null,"abstract":"<p><p>We herein report the synthesis, and antiproliferative evaluation of a novel series of N(4)-substituted 5,7-dibromoisatin thiosemicarbazones (TSCs). Structure and activity based approach was used to synthesize derivatives: N(4)-pyrrolidinyl (L1), N(4)-piperidinyl (L2), N(4)-morpholinyl (L3), N(4)-methyl (L4), and N(4)-ethyl (L5). The compounds were characterized by elemental analysis, FTIR, ¹H NMR, ¹³C NMR, UV-Vis spectroscopy, HRMS and single crystal X-ray analysis. The antiproliferative activity of the synthesized TSCs was evaluated in a dose-dependent manner against breast (MCF-7, MDA-MB-231), skin (A431), lung (A549, NCI-H460), and prostate (PC3) cancer cell lines. L3 and L5 exhibited enhanced cytotoxicity in the low micromolar range of IC₅₀; 1.16-2.47 µM. Notably, L5 showed superior potency in MCF-7 cells with IC₅₀; 1.16 µM compared to the FDA-approved thiosemicarbazone Triapine with IC₅₀; 4.27 µM, while displaying minimal toxicity toward non-tumorigenic MCF-10a breast epithelial cells with selectivity index > 86.20, consistent with ADMET predictions. Molecular docking and molecular dynamics simulations demonstrated stronger binding affinity and greater complex stability of L5 with PTOV1 compared to the FDA approved drug Lenalidomide, supporting L5 drug likeness and therapeutic potential. Mechanistic investigations through functional assays like crystal violet assays, flow cytometry, immunoblotting, and microscopy revealed that L5 induces G0/G1 cell-cycle arrest, suppresses cell migration, invasion, colony formation, 3D spheroid growth, and promotes apoptotic cell death in MCF-7. Western blot analysis provided direct mechanistic evidence that L5 downregulates PTOV1 expression, leading to reduced phosphorylation of AKT1/2/3 and c-Jun, reduced β-catenin nuclear translocation, and decreased MMP-2 expression. L5 enhanced H2AX phosphorylation, suppressed PARP and BCL-XL levels, and increased active caspase-3 driving L5 induced apoptosis. This study identifies L5 as a potent anticancer agent in breast cancer, acting through modulation of the PTOV1-AKT-β-catenin signaling axis, and highlights PTOV1 as a promising therapeutic target.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70306"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147867097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor Activity of Sodium Selenite, Palbociclib, and Disulfiram Against Osteosarcoma and Rhabdomyosarcoma Cell Lines.","authors":"María Ángeles Chico, Kevin Doello, Raul Ortiz, Mercedes Peña, Consolación Melguizo, Cristina Mesas, Jose Prados","doi":"10.1002/ddr.70304","DOIUrl":"10.1002/ddr.70304","url":null,"abstract":"<p><p>Osteosarcoma and rhabdomyosarcoma are the most common pediatric sarcomas, yet prognosis remains poor due to high relapse rates. This study investigates the repurposing of palbociclib (PB) and disulfiram (DS), alongside sodium selenite (SS), as potential therapeutic strategies. Using cell lines, we assessed antiproliferative effects via Sulforhodamine B, colony formation, and wound healing assays. Mechanisms of action were explored through protein expression of PARP-1 (apoptosis) and LC3β (autophagy), qPCR for stem cell markers, and ROS quantification. Finally, antitumor and anti-angiogenic efficacy was validated using the in ovo chicken chorioallantoic membrane (CAM) assay. Results demonstrated that all three compounds inhibited proliferation, migration, and spheroid growth while inducing apoptosis and autophagy. Notably, SS and PB elevated ROS levels, triggering parthanatos-mediated cell death via AIF nuclear translocation. SS also exhibited significant anti-angiogenic activity. Xenograft CAM models confirmed the in vivo efficacy of SS, PB, and DS against RD and MG63 cells. These findings suggest that SS, PB, and DS are promising candidates for pediatric sarcoma treatment, particularly as maintenance therapies to prevent relapse following conventional radical treatment.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70304"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812473","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, Green Synthesis, and Biological Evaluation of Novel Triaryl-Tethered Acryloyl Derivatives as New Generation β-Tubulin Inhibitors for Hepatocellular Carcinoma Treatment","authors":"Aamal A. Al-Mutairi,&nbsp;Mai A. E. Mourad,&nbsp;Arwa sultan Alqahtani,&nbsp;Ayman Abo Elmaaty,&nbsp;Islam Zaki","doi":"10.1002/ddr.70303","DOIUrl":"10.1002/ddr.70303","url":null,"abstract":"<div>\u0000 \u0000 <p>Inhibition of β-tubulin polymerization has been set as promising therapeutic strategy for cancer therapy. Accordingly, a new set of triaryl-tethered acetohydrazide-acryloyl derivatives were designed and synthesized. The antiproliferative influence was evaluated against liver Huh-7 cell line using MTT colorimetric method with Doxorubicin as a positive control. Compounds <b>3b</b>, <b>4f</b>, <b>4i,</b> and <b>4j</b> showed excellent cytotoxic activity against Huh-7 cell line. Among the investigated compounds, 2-(naphthalene-2-yloxy)acetohydrazide having 2-(4-methyl)-3-(3,4,5-trimethoxybenzamido)acryloyl moiety (compound <b>4i</b>) was the most active one with an IC₅₀ value of 2.46 µM. In addition, all compounds were further evaluated in vitro for their β-tubulin polymerization inhibition activity. Results found that compound <b>4i</b> showed high activity against β-tubulin polymerization with an IC₅₀ value of 2.29 µM, surpassing the activity of the reference Podophyllotoxin (IC₅₀ = 4.45 µM). Further studies revealed the ability of the promising compound <b>4i</b> to induce apoptosis and halt the cellular cycle at G2/M phase. Furthermore, the apoptosis-inducing activity of naphthalene-tethered acryloyl moiety <b>4i</b> was correlated to the downregulation of Bcl-2 as well as elevation of both Bax and <i>c</i>aspase 9 as concluded from RT-PCR immunoassay measurements. Finally, molecular docking studies were also performed to explain the displayed inhibitory activities.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Development of Chemical Probes for Targeting Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitors","authors":"Kadalipura P. Rakesh,&nbsp;Santosh Kumar Verma,&nbsp;Man Vir Singh,&nbsp;Abdulwahab Abuderman,&nbsp;Shekhar Verma,&nbsp;Rameshwari Verma,&nbsp;Sangeeta Soni","doi":"10.1002/ddr.70302","DOIUrl":"10.1002/ddr.70302","url":null,"abstract":"<div>\u0000 \u0000 <p>As a transcriptional coactivator and associated arginine methyltransferase 1, CARM1 controls various biological functions. CARM1 was thought to be a prospective therapeutic target, as anomalous appearance of the gene has been linked to the development of several cancer types. Since there aren't any CARM1 inhibitors available for use in clinical trials at the moment, Kindle is interested in the development of human pharmacological treatments that target CARM1. To confirm this PRMT as a therapeutic target, selective inhibitors of CARM1 would be helpful tools. In this review, we discuss the identification, description, and biological use of CARM1 inhibitors, focusing on significant developments in the field.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained DNA Hypomethylation Induced by a DNA Methyltransferase 1 Inhibitor Triggers Apoptosis in Thyroid Cancer Cells","authors":"Chao-Wen Cheng,&nbsp;Wen-Fang Fang,&nbsp;Yuan-Hung Wang,&nbsp;Yea-Mey Yang,&nbsp;Jiunn-Diann Lin","doi":"10.1002/ddr.70299","DOIUrl":"10.1002/ddr.70299","url":null,"abstract":"<div>\u0000 \u0000 <p>DNA methylation, is catalyzed by DNA methyltransferases (DNMTs), and its aberrant patterns are implicated in thyroid cancer pathogenesis. The study aimed to investigate the association of DNMTs with thyroid cancer and evaluated the effects of sustained demethylating therapy in a cell-based study. DNMTs expressions in thyroid cancer were analyzed using GEO and TCGA datasets. Additionally, 16 paired and three unpaired papillary thyroid carcinoma (PTC) samples from Taipei Medical University (TMU), along with commercial tissue arrays, were analyzed. Furthermore, the effects of the covalent DNMT inhibitor, 5-azacytidine (5-Aza), and the DNMT1-selective inhibitor, GSK-3484862, on cell viability were evaluated in PTC and follicular thyroid carcinoma (FTC) cell lines. DNMT1 and DNMT3A were upregulated in PTC, with DNMT1 expression correlated with the <i>BRAF</i> mutation and lymph node invasion in TCGA data, findings further confirmed in the TMU cohort and tissue arrays. Short-term (24 h) 5-Aza treatment (1 and 5 µM) induced substantial cell death regardless of the DNA methylation status, whereas short-term GSK-3484862 (5 µM) treatment showed minimal cytotoxicity. In contrast, sustained low-dose GSK-3484862 treatment (approximately 1–3 weeks at 2 µM) effectively reduced global DNA methylation and decreased cell viability of TPC-1 and FTC-236 cells through apoptosis, rather than by inhibiting proliferation. In conclusion, DNMT1 overexpression in PTC suggests its involvement in thyroid carcinogenesis. Sustained inhibition of DNMT1 effectively reduced global DNA methylation and promoted apoptosis, highlighting the potential of prolonged DNMT1-targeted therapy. Further in vitro and in vivo studies are warranted to validate these results and elucidate the underlying mechanisms.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitexicarpin Directly Targets RSK2 to Attenuate Migration and Invasion of Triple-Negative Breast Cancer Through Modulating HIF-1α/MMP-9 Pathway","authors":"Shuhui You,&nbsp;Tianhui Wu,&nbsp;Min Qian,&nbsp;Jiahui Du,&nbsp;Wenbing Sun,&nbsp;Mengyao Li,&nbsp;Xiaocan Zhang,&nbsp;Yuyang Zhou,&nbsp;Liangzhi Li,&nbsp;Min Xiang,&nbsp;Weiqiang Guo","doi":"10.1002/ddr.70291","DOIUrl":"10.1002/ddr.70291","url":null,"abstract":"<div>\u0000 \u0000 <p>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high metastatic potential and lacking effective treatment strategies. Vitexicarpin (VIT) has been reported to have excellent inhibitory effects on several types of cancer, including TNBC. However, its potential mechanisms on metastatic TNBC are not well understood. Herein, we found that VIT inhibited migration and invasion of TNBC through reducing MMP-9 expression in vitro and in vivo. Subsequently, RSK2 was identified as the potential target of VIT in TNBC by pull-down and MS analysis. Moreover, the further validations showed that VIT bound to Asp148 and Asp154 residues of NTKD, and Thr493 of CTKD, thereby inhibiting its phosphorylation and kinase activity. Mechanistically, we found that HIF-1α/MMP-9 was involved in VIT-mediated inhibition of migration and invasion of TNBC, and similar results were observed upon RSK2 knockdown or combined with VIT treatment, which demonstrated that VIT-mediated inhibition of HIF-1α/MMP-9 pathway was dependent on targeting RSK2. Finally, TNBC mouse xenograft models showed that VIT effectively inhibited TNBC metastasis and growth through regulating the RSK2/HIF-1α/MMP-9 axis in vivo. Taken together, our findings demonstrated that VIT downregulated the HIF-1α/MMP-9 pathway to suppress TNBC migration and invasion by directly targeting RSK2. These results suggested that VIT is a potential drug candidate for TNBC treatment.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}