European Journal of Medicinal Chemistry最新文献_第5页

ATM inhibitors in cancer radiotherapy: Mechanisms, clinical development, and future directions 肿瘤放疗中的ATM抑制剂：机制、临床发展和未来方向

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-04 DOI: 10.1016/j.ejmech.2025.118137

Raed M. Al-Zoubi , Khalil Garada , Reem Al Huneidi , Zaid M.H. Baddar , Ayman A. Zarour , Mai Elaarag , Sally R. Al-Zoubi , Ahmad R. Al-Qudimat , Mazhar Salim Al Zoubi , Abdelali Agouni , Khalid Alrumaihi

{"title":"ATM inhibitors in cancer radiotherapy: Mechanisms, clinical development, and future directions","authors":"Raed M. Al-Zoubi , Khalil Garada , Reem Al Huneidi , Zaid M.H. Baddar , Ayman A. Zarour , Mai Elaarag , Sally R. Al-Zoubi , Ahmad R. Al-Qudimat , Mazhar Salim Al Zoubi , Abdelali Agouni , Khalid Alrumaihi","doi":"10.1016/j.ejmech.2025.118137","DOIUrl":"10.1016/j.ejmech.2025.118137","url":null,"abstract":"<div><div>Ataxia-telangiectasia mutated (ATM) kinase plays a pivotal role in the cellular response to DNA damage. Under normal conditions, ATM acts as a tumor suppressor by regulating pathways that lead to apoptosis and cell cycle arrest via effectors like p53, p21, CHK1, and CHK2. Paradoxically, in some cancers, ATM promotes tumor cell survival and metastasis, especially when aberrantly activated, linking it to therapy resistance and poor outcomes. Its involvement in both radiotherapy and chemotherapy has made ATM an attractive target for cancer treatment. Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy. A key challenge remains the development of ATM inhibitors that can effectively cross the blood-brain barrier for use against brain tumors. Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118137"},"PeriodicalIF":5.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995171","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}

引用次数: 0

Intramolecular Hydrogen-Bonding Motifs in the 14-Oxymorphinan Opioids: An Experimental and Computational Study 14-Oxymorphinan类阿片分子内氢键基序：实验和计算研究

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-04 DOI: 10.1016/j.ejmech.2025.118133

Dina Yeffet, Ishay Columbus, Naama Lifshin-Karton, Shlomi Elias, Sigal Saphier, Alexander Pevzner, Yoram Cohen, Yoav Eichen, Galit Parvari, Yossi Zafrani

{"title":"Intramolecular Hydrogen-Bonding Motifs in the 14-Oxymorphinan Opioids: An Experimental and Computational Study","authors":"Dina Yeffet, Ishay Columbus, Naama Lifshin-Karton, Shlomi Elias, Sigal Saphier, Alexander Pevzner, Yoram Cohen, Yoav Eichen, Galit Parvari, Yossi Zafrani","doi":"10.1016/j.ejmech.2025.118133","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118133","url":null,"abstract":"Increasing the molecular rigidity of bioactive compounds by intramolecular hydrogen bonds (IMHB) may affect both pharmacodynamics (PD) and pharmacokinetics (PK) by an increase in molecular recognition, lipophilicity and membrane permeability. Recently, in our study on opioids lipophilicity, we suggested two types of IMHBs, i.e., O-H<sup>…</sup>N and N<sup>+</sup>-H<sup>…</sup>O, which may exist in 14-oxymorphinan structures and may explain some trends and even apparent anomalies in their pharmacologically relevant molecular properties. In the present study we show, both experimentally and computationally, that these IMHBs indeed exist in the three FDA-approved opioid antagonists, Naloxone, Naltrexone and Nalmefene, as well as in their 3-<em>O</em>- and 14-<em>O</em>-methylated derivatives. Since the charged form of these morphinans is the biologically active species, we propose that the charge-assisted IMHB (CAHB) N<sup>+</sup>-H<sup>…</sup>O, which is herein studied for the first time, plays an important role in the bioactivity of this subfamily of opioids.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995169","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}

引用次数: 0

Targeted degradation of Werner syndrome helicase (WRN) via ligand-directed covalent hydrophobic tagging 通过配体定向共价疏水标记靶向降解Werner综合征解旋酶（WRN）

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-04 DOI: 10.1016/j.ejmech.2025.118121

Wenxiang Tao , Jiacheng Zhu , Zixuan Fu, Xiangchi Liu, Shunlin Tang, Hua Xiang, Guoshun Luo

{"title":"Targeted degradation of Werner syndrome helicase (WRN) via ligand-directed covalent hydrophobic tagging","authors":"Wenxiang Tao , Jiacheng Zhu , Zixuan Fu, Xiangchi Liu, Shunlin Tang, Hua Xiang, Guoshun Luo","doi":"10.1016/j.ejmech.2025.118121","DOIUrl":"10.1016/j.ejmech.2025.118121","url":null,"abstract":"<div><div>The Werner syndrome RecQ helicase (WRN) has recently emerged as a novel synthetic lethality target for microsatellite instability-high (MSI-H) cancers. However, available WRN inhibitors or degraders is still lacking so far. Particularly, chemically designed probes capable of degrading WRN irrespective of microsatellite status remain unexplored. Herein, we developed an innovative ligand-directed covalent hydrophobic tagging (LdCHT) strategy leveraging a proximity-activated sulfonamide pyrimidine warhead to achieve precise WRN proteolysis. LdCHT 14c demonstrated high selectivity for WRN and induced phenotype-agnostic WRN degradation across MSI-H and microsatellite stability (MSS) cells. Mechanistic studies revealed that 14c covalently conjugates to C727 within the WRN helicase domain, forming an adamantane-tagged adduct that initiates sustained proteasomal degradation. Notably, 14c demonstrated superior efficacy over the parental WRN inhibitor in suppressing MSI-H cell growth and migration by inducing more profound transcriptional regulation. This study presents a first-in-class WRN degrader to interrogate the atypical roles of WRN and expands the covalent hydrophobic tagging toolbox for biomedical applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118121"},"PeriodicalIF":5.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995173","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}

引用次数: 0

Discovery of novel xanthotoxin-pyridine quaternary ammonium derivatives with membrane-targeting mode of action as potential antimicrobials against methicillin-resistant Staphylococcus aureus 具有膜靶向作用模式的新型黄嘌呤-吡啶季铵衍生物作为抗甲氧西林耐药金黄色葡萄球菌的潜在抗菌剂的发现

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-04 DOI: 10.1016/j.ejmech.2025.118139

Shengnan Xu , Miaomiao Zhang , Xinyu Xie , Yue Tian , Yan Wang , Xiaozhong Wang , Ruige Yang , Yong Guo

{"title":"Discovery of novel xanthotoxin-pyridine quaternary ammonium derivatives with membrane-targeting mode of action as potential antimicrobials against methicillin-resistant Staphylococcus aureus","authors":"Shengnan Xu , Miaomiao Zhang , Xinyu Xie , Yue Tian , Yan Wang , Xiaozhong Wang , Ruige Yang , Yong Guo","doi":"10.1016/j.ejmech.2025.118139","DOIUrl":"10.1016/j.ejmech.2025.118139","url":null,"abstract":"<div><div>Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) is a major global health threat owing to its multi-drug resistance, creating an urgent need for novel antibiotics. This study focused on developing anti-MRSA agents by designing and synthesizing 30 xanthotoxin-pyridine quaternary ammonium derivatives, followed by evaluating their antibacterial activity and dissecting their mechanism of action against MRSA. Among all derivatives, <strong>III13</strong> demonstrated as the most promising candidate: it exhibited potent anti-MRSA activity (MIC = 1 μg/mL), low cytotoxicity, minimal hemolysis, rapid bactericidal effects, and the ability to disrupt biofilms. Mechanistically, transcriptomics analyses showed <strong>III13</strong> inhibited DNA replication-related genes and impaired cell membrane function; further studies confirmed it targeted phosphatidylglycerol (PG) in bacterial membranes, which compromised membrane integrity and induced DNA leakage and oxidative stress. Moreover, <strong>III13</strong> displayed excellent efficacy and safety in MRSA-infected mouse models (skin abscesses and sepsis), with performance comparable to vancomycin. Collectively, these results highlight <strong>III13</strong> as a promising lead compound for the clinical treatment of MRSA infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118139"},"PeriodicalIF":5.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983393","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}

引用次数: 0

A novel strategy for combating multidrug-resistant bacteria: Natural products from uncultured microorganisms 对抗多重耐药细菌的新策略：来自未培养微生物的天然产物

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-04 DOI: 10.1016/j.ejmech.2025.118119

Ying-Ying Yang , Fang-Jing He , Shi-Yu Xie , Xing-Wei Luo , Xu Wang

{"title":"A novel strategy for combating multidrug-resistant bacteria: Natural products from uncultured microorganisms","authors":"Ying-Ying Yang , Fang-Jing He , Shi-Yu Xie , Xing-Wei Luo , Xu Wang","doi":"10.1016/j.ejmech.2025.118119","DOIUrl":"10.1016/j.ejmech.2025.118119","url":null,"abstract":"<div><div>The emergence of bacterial resistance has severely compromised the efficacy of antibiotics, creating an urgent public health crisis. Regrettably, conventional natural products (NPs), nature's primary reservoir for antibiotic discovery, are being exhausted due to overexploitation, leading to a concerning scarcity of developable NPs. There is an urgent need for new strategies to combat infections caused by drug-resistant bacteria. Of particular significance is the emerging recognition that the uncultured microbial majority in natural environments may synthesize antimicrobial compounds with unprecedented structural motifs and functional attributes capable of bypassing existing cross-resistance patterns, thereby maintaining potency against resistant pathogens—a revelation that reinvigorates the therapeutic pipeline with newfound optimism. Here, this review comprehensively and systematically expounds the newest methods for cultivating uncultured microorganisms and the action mechanisms of antibiotics from uncultured microorganisms in recent years. These antibiotics effectively bypass the multidrug resistance barrier, demonstrate excellent antibacterial activity, and show minimal resistance at present. Furthermore, they have served as novel chemical scaffolds for the development of numerous derivatives with good antibacterial activity. In summary, these antibiotics are highly unique, indicating strong potential for development and application. The NPs from uncultured microorganisms hold a great promise in addressing the issue of antibiotic resistance, providing strategic directions for the development of novel antimicrobial drugs and alleviating the resistance crisis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118119"},"PeriodicalIF":5.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995177","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}

引用次数: 0

Dual inhibition of carbonic anhydrase IX and glutathione peroxidase 4 as a novel strategy for ferroptosis-induced tumor cell death 碳酸酐酶IX和谷胱甘肽过氧化物酶4的双重抑制作为铁中毒诱导肿瘤细胞死亡的新策略

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-02 DOI: 10.1016/j.ejmech.2025.118107

Gioele Renzi , Paul C. McDonald , Shannon Awrey , Hossein Tavakoli , Zahra Bokhari , Michael Lyle , Zaihui Zhang , Marta Ferraroni , Shoukat Dedhar , Claudiu T. Supuran , Andrea Angeli

{"title":"Dual inhibition of carbonic anhydrase IX and glutathione peroxidase 4 as a novel strategy for ferroptosis-induced tumor cell death","authors":"Gioele Renzi , Paul C. McDonald , Shannon Awrey , Hossein Tavakoli , Zahra Bokhari , Michael Lyle , Zaihui Zhang , Marta Ferraroni , Shoukat Dedhar , Claudiu T. Supuran , Andrea Angeli","doi":"10.1016/j.ejmech.2025.118107","DOIUrl":"10.1016/j.ejmech.2025.118107","url":null,"abstract":"<div><div>In this study, we explored a dual-target strategy combining the inhibition of human carbonic anhydrase IX (hCA IX), a tumor-associated isoform, and glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. We demonstrated that the simultaneous inhibition of hCA IX and GPX4 disrupts redox and iron homeostasis, thereby enhancing cell death via ferroptosis. Three series of compounds were rationally designed and synthesized based on the ML162 scaffold using an integrated structural approach and their enzymatic inhibition was evaluated <em>in vitro</em>. Several dual-target compounds exhibited significant antitumor activity, with 18a–c, 22abab and 22abcb inducing dose-dependent cell death. In vivo, intratumoral administration of the lead active compound, 22abcb, significantly prevented the growth of CA IX-expressing human breast cancer xenografts, compared to inactive 22abbb. The effect on tumour growth was significantly reversed by the ferroptosis inhibitor, Fer-1, confirming ferroptosis as the underlying mechanism. These findings highlight the synergistic potential of dual-target inhibitors in disrupting tumor-specific metabolic pathways and position them as a promising therapeutic strategy for solid tumors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118107"},"PeriodicalIF":5.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931029","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}

引用次数: 0

Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy 2-四氢异喹啉取代喹唑啉衍生物作为赖氨酸甲基转移酶G9a体内抗肿瘤抑制剂的发现

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-02 DOI: 10.1016/j.ejmech.2025.118113

Mengjie Shao , Lixin Gao , Jiahui Xu , Lingfeng Zhu , Yiting Lu , Kailong Jiang , Jia Sun , Xiaolong Jiang , Jia Li , Ao Zhang , Yubo Zhou , Chunyong Ding

{"title":"Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy","authors":"Mengjie Shao , Lixin Gao , Jiahui Xu , Lingfeng Zhu , Yiting Lu , Kailong Jiang , Jia Sun , Xiaolong Jiang , Jia Li , Ao Zhang , Yubo Zhou , Chunyong Ding","doi":"10.1016/j.ejmech.2025.118113","DOIUrl":"10.1016/j.ejmech.2025.118113","url":null,"abstract":"<div><div>Overexpression of protein lysine methyltransferase G9a, which catalyzes mono- and di-methylation of histone H3K9 and non-histone proteins, is closely associated with poor prognosis and metastasis of various cancers. Here, we designed and synthesized a series of novel G9a inhibitors bearing 2-tetrahydroisoquinoline substituted quinazoline scaffold. Among them, compound <strong>31</strong> with 2-dioxole fused tetrahydroisoquinoline exhibited the most potent inhibitory effects against G9a with an IC<sub>50</sub> value of 0.032 μM and high selectivity against the other tested lysine/arginine methyltransferases. Molecular docking showed that the bulky tricyclic moiety of compound <strong>31</strong> enhanced its interaction with the active sites of G9a through additional van der Waals forces. Compared to the reference compound UNC0642, compound <strong>31</strong> exhibited much improved enzymatic activity against G9a and more potent antiproliferative effects against all tested cancer cells. In CT26 colon cells, this compound not only significantly suppressed the H3K9me2 level, but also triggered autophagy by inducing the production of ROS, thus leading to cell apoptosis and cell cycle arrest at G0/G1. It also possessed good microsomal metabolic stability and acceptable in vivo pharmacokinetic properties. More importantly, in the CT26 tumor mouse model, compound <strong>31</strong> demonstrated in vivo antitumor efficacy with a TGI rate of 45.10 % without significant body weight loss and visible toxicity, indicating a superior safety profile compared to UNC0642. Overall, compound <strong>31</strong> with 2-tetrahydroisoquinoline substituted quinazoline scaffold could be used as a promising lead compound for the development of novel G9a inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118113"},"PeriodicalIF":5.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928592","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}

引用次数: 0

Emerging opportunities and challenges in small molecule development for non-HSP90 chaperones 非hsp90伴侣蛋白小分子发展的机遇和挑战

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-08-31 DOI: 10.1016/j.ejmech.2025.118100

Meilun Tang , Qiuyu Wu , Yufei Liu , Xinyu Liu , Qidong You , Lei Wang

引用次数: 0

Discovery and SAR study of highly selective and potent 1,2,4-oxadiazole-based S1PR1 agonists 基于1,2,4-恶二唑的高选择性强效S1PR1激动剂的发现和SAR研究

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-08-30 DOI: 10.1016/j.ejmech.2025.118097

Tianyu Ye , Jinling Yu , Yuxian Fang , Zhongping Xu , Shanshan Guo , Zhenjiang Zhao , Honglin Li , Huan He , Lili Zhu

{"title":"Discovery and SAR study of highly selective and potent 1,2,4-oxadiazole-based S1PR1 agonists","authors":"Tianyu Ye , Jinling Yu , Yuxian Fang , Zhongping Xu , Shanshan Guo , Zhenjiang Zhao , Honglin Li , Huan He , Lili Zhu","doi":"10.1016/j.ejmech.2025.118097","DOIUrl":"10.1016/j.ejmech.2025.118097","url":null,"abstract":"<div><div>Sphingosine-1-phosphate receptor 1 (S1PR1) is a validated therapeutic target for immune-mediated diseases such as multiple sclerosis and ulcerative colitis, owing to its critical role in regulating of lymphocyte migration. However, the clinical utility of current S1PR1 agonists is often limited by cardiovascular adverse effects, particularly dose-dependent bradycardia. Enhancing receptor subtype selectivity represents a promising strategy to mitigate these risks. Herein, we describe the discovery and optimization of a novel series of 1,2,4-oxadiazole-based S1PR1 agonists. Among these, <strong>Y18</strong> exhibited potent agonistic activity toward S1PR1 (EC<sub>50</sub> = 0.98 nM) with >10,000-fold selectivity over S1PR2, S1PR3, and S1PR5, as well as 109-fold selectivity over S1PR4. Functional studies demonstrated that <strong>Y18</strong> efficiently induced S1PR1 internalization, blocked receptor recycling, and activated downstream ERK1/2 phosphorylation. The excellent selectivity across the S1PR family, along with its functional profile, supports <strong>Y18</strong> as a promising candidate for S1PR1-targeted therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118097"},"PeriodicalIF":5.9,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919164","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}

引用次数: 0

Fluorescence-guided tumor resection with a cathepsin B-activatable, EGFR-targeted probe and a dual-mode surgical exoscope 荧光引导肿瘤切除术与组织蛋白酶b活化，egfr靶向探针和双模式手术外窥镜

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-08-30 DOI: 10.1016/j.ejmech.2025.118108

Yejin Sung , Youngjin Choi , Sang Mi Park , Nakwon Choi , Sangmin Lee , Seung Beum Suh , Chansoo Kim , Wooyoung Hur , Seung-Woo Cho , Deukhee Lee , Ju Hee Ryu

{"title":"Fluorescence-guided tumor resection with a cathepsin B-activatable, EGFR-targeted probe and a dual-mode surgical exoscope","authors":"Yejin Sung , Youngjin Choi , Sang Mi Park , Nakwon Choi , Sangmin Lee , Seung Beum Suh , Chansoo Kim , Wooyoung Hur , Seung-Woo Cho , Deukhee Lee , Ju Hee Ryu","doi":"10.1016/j.ejmech.2025.118108","DOIUrl":"10.1016/j.ejmech.2025.118108","url":null,"abstract":"<div><div>Fluorescence-guided surgery enhances surgical precision by enabling real-time tumor visualization. Here, we developed a cathepsin B-activatable imaging probe conjugated to the EGFR-targeting antibody cetuximab (Cetux-CB probe) for fluorescence-guided resection of triple-negative breast cancer (TNBC). The probe consists of a cathepsin B-sensitive peptide linker, a near-infrared fluorophore (Flamma™ Fluors 749), and a quencher (qFlamma Black01), enabling enzymatic activation following tumor-specific accumulation. The Cetux-CB probe exhibited robust cathepsin B-dependent fluorescence activation in EGFR-overexpressing TNBC cells and xenograft tumors, with high tumor accumulation and minimal background in normal tissues. Following systemic administration, the probe demonstrated prolonged and confined fluorescence <em>in viv</em>o, outperforming both non-targeted and always-on fluorescent controls. When combined with a dual-mode surgical exoscope, the probe allowed precise intraoperative tumor localization and guided accurate incision and dissection, confirmed by the absence of residual signal. This study demonstrates the clinical potential of combining dual-responsive imaging probes with compatible imaging systems to improve surgical outcomes in TNBC and other EGFR-positive cancers.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118108"},"PeriodicalIF":5.9,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919167","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}

引用次数: 0