European Journal of Medicinal Chemistry最新文献

{"title":"From molecular design to immune remodeling: Advances in perylene diimide-based multimodal cancer therapies","authors":"Lina Fu ,&nbsp;Chun'e Liu ,&nbsp;Xin Yue ,&nbsp;Tong Xu ,&nbsp;Wenhan Jia ,&nbsp;Xin Jin ,&nbsp;Junfeng Huo","doi":"10.1016/j.ejmech.2025.118545","DOIUrl":"10.1016/j.ejmech.2025.118545","url":null,"abstract":"<div><div>Perylene diimide (PDI) is a programmable theranostic platform that combines high photostability with facile medicinal-chemistry modification at the imide and bay positions. Recent advances in donor–acceptor tuning, π-conjugation extension/fusion, and aggregation control have pushed its absorption into the near-infrared II (NIR-II) window (1000–1700 nm), and enabled programmable partitioning between photothermal conversion and Type I/II photodynamic pathways under low irradiance. This review primarily surveys PDI derivatives reported from 2015 through 2025. We focus on mechanisms that move beyond conventional phototherapy: side-chain and topological designs enable precise localization to mitochondria, lysosomes, endoplasmic reticulum (ER), and nucleus, thereby coupling metabolic/oxidative-stress reprogramming, inducing ferroptosis, and potentially overcoming multidrug resistance; Nucleus-targeted PDI acts as a selective G-quadruplex (G4) stabilizer and dsDNA binder, stabilizing G4 structures in the c-MYC promoter and at telomeres/telomerase-associated sites to downregulate oncogenic transcription and provide light-independent chemotherapeutic potential. On the immunomodulation front, acute mitochondria-localized injury triggers immunogenic cell death (ICD) and releases mitochondrial DNA (mtDNA) to activate the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway; inhibiting ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) to prolong cyclic GMP–AMP (cGAMP) persistence sustains pathway activation and converts “cold” tumors into “hot” phenotypes responsive to immune checkpoint blockade. Altogether, guided by structure–aggregation–spectrum–function relationships, we map programmable links between NIR responses, excited-state energy dissipation, and immune remodeling, and we outline design principles for evolving this molecular scaffold into a streamlined single-molecule platform that integrates chemotherapy, metabolic intervention, and immune activation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118545"},"PeriodicalIF":5.9,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881570","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 of heparin antagonist: Guanidine-based mimetics unveil key carbohydrate-carbohydrate interactions","authors":"Ankita Chandra ,&nbsp;Ana Gimeno ,&nbsp;María Payá-García ,&nbsp;Preeti Ravindra Bhoge ,&nbsp;Virendrasinh Mahida ,&nbsp;Jesús Jiménez-Barbero ,&nbsp;Raghavendra Kikkeri","doi":"10.1016/j.ejmech.2025.118551","DOIUrl":"10.1016/j.ejmech.2025.118551","url":null,"abstract":"<div><div>Small-molecule inhibitors targeting heparin (HP)-protein interactions represent a promising strategy for developing therapeutic agents against serious bleeding complications. Herein, we report a rational design and synthesis of a library of eight trisaccharide HP mimetics incorporating positively charged guanidinium residues aimed at disrupting the ionic interactions of HP and modulating HP-mediated biological activities. The introduction of guanidine residue in HP backbone significantly influenced the conformational plasticity of <span>l</span>-idose and <span>l</span>-iduronic acid, shifting the major ⁴C₁-conformation to predominant ²S₀-geometries, akin to the role of high sulfation in native HS. Unlike aminoglycosides, the guanidine-based HP mimetics exhibited no antibacterial activity and demonstrated low cytotoxicity towards both cancerous and normal cell lines. When evaluated as potential antidotes for heparin and fondaparinux-mediated blood coagulation, the highly guanidine-substituted HP mimetics displayed sub-micromolar antagonist potency. NMR studies further confirmed the carbohydrate–carbohydrate interactions between fondaparinux and the HP mimetics, providing a mechanistic basis for the observed activity and introducing a new strategy to block HP-mediated biological functions.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118551"},"PeriodicalIF":5.9,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895283","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":"LL-37-derived peptide shows promising antimicrobial potential against multidrug-resistance pathogens","authors":"Demeke Asmamaw ,&nbsp;Huajun Cai ,&nbsp;Prateeksha Prateeksha ,&nbsp;Mehwish Khalid ,&nbsp;James Mwangi ,&nbsp;Wang Yi ,&nbsp;Quimin Lu ,&nbsp;Ren Lai ,&nbsp;Zilei Duan","doi":"10.1016/j.ejmech.2025.118547","DOIUrl":"10.1016/j.ejmech.2025.118547","url":null,"abstract":"<div><div>The increasing prevalence of multidrug-resistant (MDR) bacterial infections poses global health challenges, highlighting the urgent need for new antimicrobial agents. The key advantages of antimicrobial peptides are their ability to rapid bactericidal activity and their low propensity for resistance development. In this study, we designed a series of antimicrobial peptides by fusing the two fragments of antimicrobial peptides Cathelicidin-BF (1–9) and LL-37 (17–29), and then tested against selected Gram-negative and Gram-positive bacterial strains. Among these peptides, KF-22 displayed potent antibacterial activity against a panel of Gram-negative and Gram-positive pathogens with MICs less than 5 μg/mL, with demonstrating low toxicity. Moreover, KF-22 exhibits rapid bactericidal activity and a low propensity to induce resistance, simultaneously showing excellent anti-biofilm and persisters activity. Mechanistic studies revealed that KF-22 induces membrane damage by targeting bacterial-specific membrane components, leading to the dissipate the proton motive force (PMF) and resulting in metabolic perturbations. Furthermore, in mice models no significant change was observed in plasma biochemical parameters between the treated and the control groups. In addition, <em>in vivo</em> studies confirmed that KF-22 are effective against drug-resistant pathogens. Taken together, the findings suggest that KF-22 is a promising candidate for further development to tackle MDR bacterial infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118547"},"PeriodicalIF":5.9,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881501","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":"Scaffold optimization trends in matrix metalloproteinase inhibitors for selective pancreatic cancer Therapy—A review","authors":"Kyathi Kolli,&nbsp;Dileep Kumar","doi":"10.1016/j.ejmech.2025.118540","DOIUrl":"10.1016/j.ejmech.2025.118540","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its dense stromal barrier, aggressive invasion, and resistance to therapy. Matrix metalloproteinases (MMPs), zinc-dependent endopeptidases responsible for extracellular matrix remodeling, play a critical role in PDAC progression, metastasis, and tumor microenvironment modulation. Consequently, selective inhibition of MMP isoforms has emerged as a promising therapeutic strategy. Early hydroxamate-based MMP inhibitors demonstrated potent activity but failed clinically due to poor selectivity, zinc chelation-related toxicity, and limited pharmacokinetic profiles. Recent medicinal chemistry efforts have focused on scaffold modification to overcome these challenges, leading to the evolution of alternative zinc-binding groups (ZBGs) such as carboxylates, phosphonates, thiols, and sulfonamides. This review systematically summarizes scaffold optimization trends in MMP inhibitors, correlating structural features with enzyme selectivity and anticancer efficacy. Structure–activity relationship (SAR) studies highlight the role of aromatic and polar substituents in enhancing binding affinity and isoform discrimination. Additionally, computational modeling, pharmacophore mapping, and molecular docking analyses provide mechanistic insights into ligand-enzyme interactions within the catalytic Zn²⁺ site. The review also discusses crystallographic data and structure-based drug design approaches that guide next-generation MMP inhibitor development. Collectively, this work emphasizes medicinal chemistry strategies for designing potent, selective, and bioavailable MMP inhibitors, thereby advancing rational therapeutic approaches for targeted PDAC management.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118540"},"PeriodicalIF":5.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895304","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 2,4-thiazolidinedione derivatives as selective AMPKα1 activators for renal ischemia-reperfusion injury therapeutics","authors":"Yuanbo Hu ,&nbsp;Yuanyuan Cao ,&nbsp;Qingsong Chen ,&nbsp;Wenhua Tan ,&nbsp;Yu Wang ,&nbsp;Yan Wu ,&nbsp;Yunzhen Deng ,&nbsp;Yanlin Wen ,&nbsp;Zhuo Chen ,&nbsp;Gaoyun Hu ,&nbsp;Junxiang Chen ,&nbsp;Qianbin Li","doi":"10.1016/j.ejmech.2025.118544","DOIUrl":"10.1016/j.ejmech.2025.118544","url":null,"abstract":"<div><div>AMP-activated protein kinase (AMPK) plays a key catalytic role in renal energy metabolism. Its activation confers renoprotection through regulating various downstream pathways. Critically, AMPKα2 activation can exacerbate renal injury by promoting uric acid deposition, highlighting the therapeutic advantage of highly selective AMPKα1 activation for renal ischemia-reperfusion injury (RIRI). Given these considerations, we established an effective screening platform to identify initial hits with AMPKα1 activity. Leveraging these hits, we designed and synthesized a series of thiazolidinedione derivatives as selective AMPKα1 activators. Among these, <strong>22f</strong> demonstrated superior <em>in vitro</em> AMPKα1 activity (EC₅₀ = 35.1 ± 1.20 nM) and selectivity (176-fold over AMPKα2), coupled with a significant protective effect in NRK-52E cells subjected to hypoxia-reoxygenation injury. Furthermore, in an RIRI mice model, <strong>22f</strong> selectively activated renal AMPKα1, significantly attenuating serum creatinine and blood urea nitrogen levels. Notably, <strong>22f</strong> outperformed the comparator <strong>991</strong> in alleviating kidney damage and reducing cellular infiltration. More importantly, our study provided compelling evidence that selective activation of AMPKα1 could effectively protect against RIRI pathogenesis. <strong>22f</strong> thus emerged as a promising lead compound for the development of novel anti-RIRI therapeutics offering potent efficacy and improved safety profile.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118544"},"PeriodicalIF":5.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895284","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":"Dual / bifunctional targeting of bromodomain and extra-terminal (BET) proteins: Expanding the paradigm of epigenetic drug discovery","authors":"Fei Jiang ,&nbsp;Huili Li ,&nbsp;Quan Sun ,&nbsp;Jiandong Huang ,&nbsp;Xianggui Chen ,&nbsp;Qian Liang ,&nbsp;Xueyuan Luo ,&nbsp;Wenbao Zhang ,&nbsp;Dandan He ,&nbsp;Xiangchun Shen","doi":"10.1016/j.ejmech.2025.118524","DOIUrl":"10.1016/j.ejmech.2025.118524","url":null,"abstract":"<div><div>Bromodomain and extra-terminal (BET) proteins function as key epigenetic regulators of oncogenic, inflammation, and immune pathways, however, their therapeutic targeting has been constrained by limitations of monofunctional inhibitors—notably compensatory resistance, narrow therapeutic indexes, and context-specific efficacy. This review delineates a paradigm shift from occupancy-based inhibition toward multidimensional bifunctional engagement, overcoming these barriers through rationally designed dual-target inhibitors (e.g., BET/HDAC, BET/kinases), catalytic degraders (PROTACs, molecular glues), and pathway-directed systems (autophagy-lysosome modulators, apoptotic reactivators, RIPTACs, and TCIPs). Advanced delivery platforms, including antibody–drug conjugates (ADCs) and stimuli-responsive nanocarriers, may enhance spatiotemporal precision and reduce systemic toxicity. By exploiting synergistic epigenetic-kinase cooperativity or leveraging ternary complex-driven degradation, these innovations are redefining the pharmacological landscape for BET proteins. Collectively, such strategies may provide durable efficacy against recalcitrant cancers, inflammatory disorders, and neurodegenerative diseases, suggesting emerging new design principles for epigenetic therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118524"},"PeriodicalIF":5.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895303","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":"Coumarin-stavudine (d4T) novel hybrid ProTides with dual-functionality and enhanced anti-HIV activity","authors":"Sahar B. Kandil ,&nbsp;Katie S. Jones ,&nbsp;Christophe Pannecouque ,&nbsp;Andrew D. Westwell","doi":"10.1016/j.ejmech.2025.118543","DOIUrl":"10.1016/j.ejmech.2025.118543","url":null,"abstract":"<div><div>Innovative anti-HIV strategies are urgently needed to address challenges in vaccine development and multidrug resistance. ProTides are a clinically validated prodrug strategy that improves nucleoside monophosphate delivery by bypassing the first phosphorylation step. Conventional ProTides employ phenol or 1-naphthol aryl groups, which release potentially toxic byproducts upon activation. We report the first use of coumarin-based fluorophores (4MU or 4TFMU) as aryl masking groups in stavudine (d4T) ProTides, creating hybrid profluorophores with dual antiviral and fluorescent tracking capabilities. Eight hybrid ProTides were synthesised and evaluated against HIV-1 (III_B) and HIV-2 (ROD) in MT-4 cells. Five ProTides retained activity in thymidine kinase deficient C8166-TK^- cells, confirming bypass of the first phosphorylation step. ProTide <strong>21</strong> showed potent activity (IC₅₀: 80 nM for HIV-1, 140 nM for HIV-2) and high selectivity indices (1549 and 923), outperforming d4T. Enzymatic activation was verified by ³¹P NMR. Surprisingly, two phosphorodiamidate derivatives were isolated, revealing a new class of phosphorodiamidating reagents enabling efficient synthesis of diamidate prodrugs. This multifunctional ProTide platform combined enhanced potency, reduced toxicity, and built-in fluorescence, offering promising avenues for next generation nucleoside and non-nucleoside ProTide and diamidate based therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118543"},"PeriodicalIF":5.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895302","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":"Medicinal chemistry perspective on quinazoline derivatives: Sustainable synthetic routes, anticancer evaluation, and SAR analysis","authors":"Sudarshini Dutta ,&nbsp;R. Rajesh ,&nbsp;P.M. Gurubasavaraja Swamy ,&nbsp;Arghya Paik ,&nbsp;Aryadipto Dasgupta ,&nbsp;Rohit Pal ,&nbsp;J. Kushal ,&nbsp;Gajjala Pavani","doi":"10.1016/j.ejmech.2025.118538","DOIUrl":"10.1016/j.ejmech.2025.118538","url":null,"abstract":"<div><div>Cancer remains a leading cause of global mortality, demanding safer and more effective therapies. Quinazoline and its derivatives have gained significant interest due to their versatile biological activity and ability to modulate multiple oncogenic pathways. Among these, EGFR and VEGFR are the primary targets, with many quinazoline derivatives showing strong inhibition at nanomolar IC₅₀ levels through hydrogen bonding and hydrophobic interactions within ATP-binding pockets. FDA-approved drugs like Gefitinib, Erlotinib, Afatinib, Dacomitinib, and Vandetanib validate the therapeutic significance of the quinazoline framework in modulating different cancer pathways. Additionally, derivatives acting on BRAF, HER2, PARP-1, COX-2, and PI3K/Akt/mTOR pathways have shown notable cytotoxic and apoptosis-inducing effects. Different synthetic strategies, including metal-catalysed, microwave-assisted, and solvent mediated methods, have been used to develop diverse quinazoline frameworks fused with rings like triazole, thiazole, oxadiazole, and pyrimidine. Structure activity relationship (SAR) analyses reveal that adding halogen, methoxy, or heteroaryl groups at specific ring positions enhance kinase affinity and cytotoxic efficacy. Overall, this review highlights recent progress linking synthetic design, molecular docking, and biological response, establishing quinazoline derivatives as promising multitargeted scaffolds for the design of next-generation anticancer agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118538"},"PeriodicalIF":5.9,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881571","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":"Chemical modification of STL427944 toward morpholine-based 1,3,5-triazines as anticancer agents targeting FOXM1: green synthesis, biological evaluation and ADME-Tox profiling in a colorectal cancer model","authors":"Damian Kułaga ,&nbsp;Natalia Bosak ,&nbsp;Magda Ptaszkiewicz ,&nbsp;Julia Chrzan ,&nbsp;Katarzyna Staroń ,&nbsp;Kamila Marzec ,&nbsp;Anna K. Drabczyk ,&nbsp;Izabela Siemieńska ,&nbsp;Marta Kot ,&nbsp;Gniewomir Latacz ,&nbsp;Joanna Karnafał ,&nbsp;Carlos A. Velázquez-Martínez ,&nbsp;Katarzyna Malarz ,&nbsp;Anna Mrozek-Wilczkiewicz ,&nbsp;Anna Boguszewska-Czubara ,&nbsp;Katarzyna Greber ,&nbsp;Krzesimir Ciura","doi":"10.1016/j.ejmech.2025.118532","DOIUrl":"10.1016/j.ejmech.2025.118532","url":null,"abstract":"<div><div>Morpholine-based 1,3,5-triazines are a promising chemotype for anticancer drug discovery, particularly through inhibition of transcription factor FOXM1, a key driver of colorectal cancer (CRC) progression. In this study, we developed an ultrasound-assisted, eco-friendly synthesis of 17 new derivatives and evaluated their activity in CRC models. Compared with conventional conditions, the sonochemical protocol offered significantly shorter reaction times, more sustainable solvent use, and improved compliance with Green Chemistry Principles. Preliminary 24-h cytotoxicity screening identified compounds <strong>14</strong> and <strong>15</strong> as the most active. Compound <strong>14</strong> showed IC₅₀ values of 14.9 μM (SW620), 17.5 μM (SW480), and 36.7 μM (CCD841), yielding favorable selectivity indices (2.1–2.5). It was more potent than 5-fluorouracil in SW620 cells (IC₅₀ = 21.7 μM). Functional assays confirmed near complete inhibition of colony formation at 3 μM and suppression of cell migration at 6.25–12.5 μM. Mechanistic studies revealed downregulation of FOXM1 and its downstream effectors CCNB1 and CDC25, resulting in G₂/M arrest and apoptosis. Additional profiling showed weak PI3Kγ inhibition (IC₅₀ = 3.5 μM), high passive permeability (P_e = 11.7 × 10⁻⁶ cm/s), and lower CYP3A4/2D6 interference compared with the reference compounds. The inhibition of colony formation and suppression of cell migration, the key features of the CSC phenotype, suggest that compound <strong>14</strong> effectively targets the populations responsible for self-renewal and metastasis. Its high activity in the CSC-rich SW620 line, including superior potency to 5-fluorouracil, further underscores its therapeutic potential for treating advanced resistant colorectal cancer. <em>In vivo</em> validation using a zebrafish xenograft model demonstrated that compound <strong>14</strong> reduced tumor growth, with the strongest effect observed in the metastatic SW620 line. Overall, compound <strong>14</strong> significantly outperformed the original <em>hit</em> (STL427944), achieving FOXM1 inhibition at &lt;12.5 μM (<em>vs.</em> 25–50 μM for STL). This marks it as a next-generation FOXM1-targeting lead, combining potent and selective anticancer activity with sustainable synthesis, and positioning it as a strong candidate for further preclinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118532"},"PeriodicalIF":5.9,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881500","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":"A photoactivatable prodrug strategy toward spatially targeted inhibition of POLRMT for anticancer therapy","authors":"Lijuan Huang ,&nbsp;Yunyue Wang ,&nbsp;Minghui Yu ,&nbsp;Xinyang Nie ,&nbsp;Yifan Yuan ,&nbsp;Bao He ,&nbsp;Zhixiang Sun ,&nbsp;Jinyi Xu ,&nbsp;Lei Shi ,&nbsp;Hong Yao ,&nbsp;Xinnan Li","doi":"10.1016/j.ejmech.2025.118537","DOIUrl":"10.1016/j.ejmech.2025.118537","url":null,"abstract":"<div><div>Mitochondrial RNA polymerase (POLRMT) is overexpressed in multiple cancer types and has emerged as a viable therapeutic target. Inhibition of POLRMT disrupts mitochondrial transcription and impairs oxidative phosphorylation (OXPHOS), ultimately suppressing cancer cell proliferation. However, conventional POLRMT inhibitors may also affect normal tissues with high metabolic demands, posing a potential risk of energy deficiency. In this study, we designed and synthesized a series of photoactivatable POLRMT inhibitors. The lead compound, <strong>J5</strong>, exhibits biological inertness in the dark and rapidly liberates the active parent molecule <strong>LJ03</strong> upon irradiation, enabling spatiotemporally precise POLRMT inhibition and localized antitumor efficacy. Controlled release of <strong>LJ03</strong> was achieved through optimization of illumination parameters, which significantly improved tissue selectivity. The antiproliferative activity of <strong>J5</strong> was further validated in a zebrafish xenograft model. Collectively, this work demonstrates the feasibility of photoactivated POLRMT inhibitors for enhancing the safety profile of POLRMT-targeting agents, highlighting a potential avenue for future precision oncology applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"304 ","pages":"Article 118537"},"PeriodicalIF":5.9,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145845452","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}