Drug Development Research最新文献

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148088011","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148088012","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":"Potential Biological Targets of Anticancer Metal-Based Drug Candidates: A Systematic Review","authors":"Allysson L. dos S. Ferreira,&nbsp;Bruna B. Dantas,&nbsp;Jailton De Souza-Ferrari,&nbsp;Edilson B. Alencar Filho","doi":"10.1002/ddr.70315","DOIUrl":"10.1002/ddr.70315","url":null,"abstract":"<p>The discovery of Cisplatin marked the beginning of the metallodrug era in oncology. Despite their clinical success, platinum-based compounds present important limitations, including drug resistance and systemic toxicity. These challenges have stimulated interest in alternative metal complexes capable of interacting with biomolecular targets beyond DNA, particularly proteins involved in cancer-related pathways. To systematically identify and categorize protein targets associated with the antitumor activity of metal complexes in preclinical studies, emphasizing their functional classification and biological relevance. A systematic search was conducted in Web of Science, Wiley, Scopus, and ScienceDirect for studies published between January 2015 and March 2025. Original studies evaluating the antitumor activity of metal complexes with experimental or computational evidence of protein-directed mechanisms were included. Reviews, editorials, theoretical studies without experimental support, and studies focused exclusively on serum albumin binding were excluded. Of the 873 records identified, 59 studies met the inclusion criteria. Reported targets were organized according to Gene Ontology–based biological processes, revealing recurrent associations with redox regulation, apoptosis and cell-cycle control, and DNA replication and repair, with fewer studies addressing angiogenesis and drug-resistance mechanisms. Across categories, mechanistic evidence is predominantly derived from in vitro assays and computational analyses, with limited demonstration of selective intracellular target engagement. Current evidence indicates that metal complexes frequently perturb survival-related cellular networks, particularly those associated with redox balance and stress-response pathways. However, the available literature remains largely preclinical and mechanistically heterogeneous, highlighting the need for more rigorous target-validation strategies to clarify the therapeutic relevance of proposed protein targets.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13181534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962480","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":"Kv1.3 Channel Blockade by Dalfampridine Attenuates NLRP3 Inflammasome-Driven Demyelination via the NEK7/Ripk1/FADD Pathway, Matching the Efficacy of Broad P2X7 Antagonism by Suramin in EAE","authors":"Ahmed S. Kamel,&nbsp;Heba Nasr Shalaby,&nbsp;Yasmin A. M. El-Said,&nbsp;Dalia A. Nawwar","doi":"10.1002/ddr.70318","DOIUrl":"10.1002/ddr.70318","url":null,"abstract":"<div>\u0000 \u0000 <p>The loss of intracellular K⁺ facilitated by different channels such as Panx1, TWIK2, or Kv1.3, is a danger signal that activates programmed cell death in oligodendrocytes via NLRP3 inflammasome and pyroptosis in multiple sclerosis (MS). ATP triggers P2X7 purinergic receptors, which coordinate TWIK-2 and Panx-1 channels. Given this hierarchical signaling architecture, the present study postulated that strategic Kv1.3 intervention using Dalfampridine (Dal) could mirror comprehensive P2X7 blockade with Suramin (Sur) in the experimental autoimmune encephalomyelitis (EAE) as MS animal model. EAE mice received either Dal (10 µg/mouse/day, oral for 2 weeks) or a single Sur injection (100 mg/kg, intraperitoneal). Both interventions demonstrated comparable efficacy in restoring motor function in open field and rotarod tests, preserving myelin integrity under Luxol fast blue stain, and attenuating neuroinflammatory infiltrates within spinal tissues. Molecular profiling confirmed EAE-associated hyperactivation of the ATP-P2X7R-K⁺ efflux cascade. Sur exerted broad-spectrum inhibition, suppressing ATP accumulation, P2X7R overexpression, and all three channels. Conversely, Dal specifically reduced Kv1.3 expression while leaving ATP levels, P2X7R, TWIK-2, and pannexin-1 unchanged. Remarkably, both compounds achieved equivalent disruption of NEK7/Ripk1/FADD/NLRP3 inflammasome complex and pyroptotic machinery, including pro-caspas1 activation and subsequent gasdermin-D cleavage. These findings suggest that Kv1.3 may serve as a contributory node where downstream channel modulation can deliver neuroprotection equivalent to the upstream pathway intervention. By modulating this potential checkpoint, Kv1.3-targeted therapy may reduce collateral effects associated with pan-purinergic blockade, offering a potential streamlined therapeutic corridor for demyelinating neuroinflammation with enhanced specificity and reduced systemic burden.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962510","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":"MORC2 Recruits Tumor-Associated Macrophages and Inhibits Pyroptosis Through Activating the Wnt/β-Catenin Pathway in Breast Cancer","authors":"Zhiyong Liu,&nbsp;Hong Hu,&nbsp;Zhiqin Lin,&nbsp;Xiaoshan Meng","doi":"10.1002/ddr.70300","DOIUrl":"10.1002/ddr.70300","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Breast cancer (BC), characterized by a high incidence specifically in women, exhibits a complex etiology. This study aims to investigate the role and underlying mechanism of <i>microrchidia CW-type zinc finger 2 (MORC2)</i> in BC progression. MCF-7 and MDA-MB-231 cells with <i>MORC2</i> knockdown were utilized to investigate the impact of <i>MORC2</i> on BC. To explore the in vivo functions of <i>MORC2,</i> xenograft tumor mouse model was established. In this study, we discovered that <i>MORC2</i> was significantly upregulated in BC tumor tissues. Consistent with MORC2 functioning as a suppressor of pyroptosis, <i>MORC2</i> knockdown enhanced the expression of pyroptosis-related markers (Caspase-1, NLRP3, GSDMD-N, and LDH) and inflammatory factors (IL-18, IL-1β, and TNF-α), while suppressing <i>CCL5, CCL2</i> levels, and macrophage migration. Furthermore, <i>MORC2</i> knockdown inhibited tumor growth in vivo, decreased CD68 cell infiltration and M2 markers, and increased the M1/M2 macrophage ratio. TAMs from <i>MORC2-</i>knockdown tumors exhibited reduced immunosuppressive capacity, promoting T cell proliferation and IFN-γ/IL-2 production. Mechanistically, silencing of <i>MORC2</i> suppressed the <i>Wnt/β-catenin</i> pathway, and Compound 3 f significantly reversed the effects of <i>MORC2</i> knockdown on pyroptosis and macrophage recruitment BC. In summary, MORC2 suppresses pyroptosis and promotes TAMs recruitment in BC; <i>MORC2</i> knockdown alleviated the progression of BC by reversing these effects, which was mediated by suppressing the <i>Wnt/β-catenin</i> signaling pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962540","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":"Nanoplatform-Based Delivery Systems for PROTACs","authors":"Wenbo Che,&nbsp;Xinlin Wang,&nbsp;Sijin Chen,&nbsp;Mao Du,&nbsp;Wenyu Wang,&nbsp;Dan Liu,&nbsp;Shuai Fan,&nbsp;Zundao Wu,&nbsp;Yi Wu,&nbsp;Yanbo Dong,&nbsp;Qin Xia","doi":"10.1002/ddr.70301","DOIUrl":"10.1002/ddr.70301","url":null,"abstract":"<div>\u0000 \u0000 <p>Proteolysis Targeting Chimera (PROTAC) is a bifunctional small molecule composed of a ligand for the target protein, a ligand for an E3 ubiquitin ligase, and a chemical linker. It induces the formation of a ternary complex between the target protein and the E3 ligase, thereby promoting ubiquitination and subsequent proteasomal degradation of the target. As an emerging targeted protein degradation (TPD) strategy, PROTACs offer notable advantages such as rapid action, sustained efficacy, and high selectivity. However, PROTACs encounter significant challenges in in vivo delivery due to their unfavorable physicochemical properties, including high molecular weight, limited membrane permeability, and poor plasma stability. In recent years, the development of nanodelivery platforms has emerged as a promising strategy to overcome these limitations, significantly enhancing the bioavailability and therapeutic efficiency of PROTACs while accelerating their clinical translation and application.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873651","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":"Design, Synthesis, Biological Evaluation, and Molecular Modeling Studies of Novel 2-Aminothiazole Derivatives as Potential FOXM1 Inhibitors for Triple-Negative Breast Cancer Therapy and Structure-Activity Relationship","authors":"Khaled A. N. Abusharkh,&nbsp;Venhar Çınar,&nbsp;Alper Onder,&nbsp;Merve Sıkık,&nbsp; Mustafa Guzel,&nbsp;Zuhal Hamurcu,&nbsp;Bulent Ozpolat,&nbsp;Mehmet Ay,&nbsp;Ferah Comert Onder","doi":"10.1002/ddr.70296","DOIUrl":"10.1002/ddr.70296","url":null,"abstract":"<p>Triple Negative Breast Cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), which is associated with a very poor prognosis. It is a broad category of tumors with a variety of biological, clinical, and morphological characteristics. FOXM1 is a pivotal transcription factor that modulates proliferation-associated genes through complex protein-DNA and protein-protein interactions, making it a highly attractive target in cancer therapy. However, existing small-molecule inhibitors often suffer from limited specificity and efficacy. In this study, we designed, synthesized, and evaluated novel series of 2-aminothiazole derivatives (<b>C1-C15)</b> as potential FOXM1 inhibitors. Molecular docking and molecular dynamics (MD) simulations were employed to investigate the binding interactions of these compounds with the FOXM1 DNA-binding domain (FOXM1-DBD). Structural analysis highlighted the importance of crucial residues, including Asn283, His287, and Arg286, in mediating inhibitory activity. Among the synthesized compounds, <b>C11</b> exhibited remarkable structural alignment and interaction patterns with FOXM1-DBD, comparable to the reference inhibitor FDI-6. In vitro studies using TNBC cell lines (MDA-MB-231, BT-549, and BT-20) demonstrated that compound <b>C11</b> significantly outperformed FDI-6 in potency. Western blot analysis revealed that <b>C11</b> effectively suppressed FOXM1 transcriptional activity at concentrations of 10 µM in BT-549 cells and 20 µM in MDA-MB-231 cells. These findings underscore the potential of <b>C11</b> as a potent FOXM1 inhibitor and highlight its promise for further development in TNBC therapy.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812504","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":"Structure-Guided Design and Mechanistic Elucidation of New Chromene Derivatives as Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitors With Potent Anticancer Activity","authors":"Hazem Elkady,&nbsp;Walid E. Elgammal,&nbsp;Ibrahim H. Eissa,&nbsp;Hazem A. Mahdy,&nbsp;Aisha A. Alsfouk,&nbsp;Fatma G. Amin,&nbsp;Dalal Z. Husein,&nbsp;Ahmed M. Metwaly,&nbsp;Eslam B. Elkaeed","doi":"10.1002/ddr.70297","DOIUrl":"10.1002/ddr.70297","url":null,"abstract":"<div>\u0000 \u0000 <p>In this study, a novel series of chromene-based derivatives was rationally designed as potential VEGFR-2 inhibitors based on key structural and pharmacophoric features required for antiangiogenic activity. Accordingly, twelve chromene derivatives (<b>13a–e, 15a–e</b>, and <b>17a–b</b>) were successfully synthesized and structurally characterized. The synthesized compounds were evaluated in vitro for their cytotoxic activity against human cancer cell lines (MCF-7, HepG-2, and HCT-116), in addition to normal WI-38 and WISH cells. Among the tested compounds, compound <b>13a</b> demonstrated the most potent and selective antiproliferative activity, exhibiting low micromolar IC₅₀ values and favorable selectivity indices. Enzymatic assays confirmed its VEGFR-2 inhibitory activity (IC₅₀ = 1.666 ± 0.025 µM), comparable to the reference drug sorafenib. Mechanistic investigations revealed that compound <b>13a</b> effectively inhibited cancer cell migration in a wound healing assay, highlighting its potential antiangiogenic properties. Furthermore, compound <b>13a</b> induced significant G0/G1 cell cycle arrest in MCF-7 cells and triggered apoptosis, as evidenced by Annexin V/PI staining. To support the experimental findings, Density Functional Theory (DFT) calculations confirmed favorable structural stability and electronic properties. Molecular docking studies demonstrated strong binding interactions within the VEGFR-2 ATP-binding site. These results were further validated by 200 ns molecular dynamics simulations, MM-GBSA binding free energy calculations, Protein–Ligand Interaction Fingerprints (Pro-LIF), Principal Component Analysis of Trajectories (PCA-T), and Free Energy Landscape (FEL) analyses, confirming the dynamic stability and favorable energetics of the VEGFR-2–<b>13a</b> complex. Overall, this integrated experimental and computational study identifies compound <b>13a</b> as a promising VEGFR-2–targeted anticancer lead warranting further preclinical investigation.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812501","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":"Heterocyclic Scaffold Modification of Chalcones: Piperidinyl and Morpholinyl Triazene Derivatives as Potent Blood Stage Antimalarials With SAR and Docking Insights.","authors":"Ahammed Ameen Thottasseri, Vinoth Rajendran, Deepthi Ramesh, Anju Agnes Tom, Afjuna Vk, Tiasa Das, Tharanikkarasu Kannan","doi":"10.1002/ddr.70313","DOIUrl":"10.1002/ddr.70313","url":null,"abstract":"<p><p>The emergence of resistance to existing antimalarials, including artemisinin and its combinations, has intensified the need for new chemotypes with improved efficacy. In this study, a scaffold-hopping strategy was employed to design and develop two series of triazene-appended chalcones, piperidinyl (PiCs) and morpholinyl (MCs), by modifying our previously reported pyrrolidinyl chalcones (PCs). Both PiC and MC series exhibited moderate to good antimalarial activity, with several derivatives showing improved potency over the parent PCs against the Plasmodium falciparum 3D7 strain. Among them, MC-22 and MC-23 were the most active, exhibiting IC₅₀ values of 1.02 and 1.13 µg/mL, respectively, while PiC-5, PiC-22, and PiC-18 also demonstrated promising activity (IC₅₀ = 3.27 to 4.60 µg/mL). Structure-activity relationship analysis highlighted enhanced activity of ortho and meta-substituted derivatives, with the exception of para-CF₃ analogues. Molecular docking confirmed favourable interactions with Plasmodium falciparum-dihydrofolate reductase, and all the hit compounds were found to be non-hemolytic. These findings highlight the effectiveness of heterocyclic scaffold modification in enhancing antiplasmodial activity and demonstrate the potential of morpholine-based triazene-chalcones as promising antimalarial agents.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70313"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926851","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":"Programmable Poly-Lactic-Co-Glycolic Acid Nanocarriers for Precision Therapy of Pancreatic Ductal Adenocarcinoma.","authors":"Shruti Gupta, Nazim Nasir, Shadma Wahab, Garima Gupta, Khang Wen Goh, Prashant Kesharwani","doi":"10.1002/ddr.70307","DOIUrl":"10.1002/ddr.70307","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, characterized by late-stage diagnosis, dense desmoplastic stroma, rapid metastatic progression, and poor responsiveness to conventional chemotherapy. Consequently, the development of effective drug delivery strategies capable of overcoming stromal and resistance barriers remains an urgent clinical priority. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles have emerged as a versatile biomaterials platform for improving therapeutic outcomes through enhanced drug solubility, sustained release, and favorable pharmacokinetics. This review critically examines recent advances in the rational design and functionalization of PLGA-based nanocarriers for PDAC therapy, with particular emphasis on tumor-targeted delivery, stromal modulation, and strategies to overcome multidrug resistance. Surface engineering approaches, including ligand conjugation and stimuli-responsive systems, have shown considerable promise in enhancing intratumoral penetration and therapeutic efficacy. In addition, advanced nanoscale analytical and interfacial characterization techniques such as dynamic light scattering, electron microscopy, and zeta potential analysis provide important mechanistic insights into particle stability, cellular interactions, and drug-polymer dynamics, thereby guiding formulation optimization. Collectively, current evidence highlights the strong translational potential of PLGA nanocarriers in precision oncology for PDAC. Continued integration of biomaterials engineering with disease-specific targeting and rigorous physicochemical characterization will be essential to accelerate clinical development and improve patient outcomes.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70307"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927229","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}