European Journal of Medicinal Chemistry最新文献

{"title":"New 3-[(tetrazol-5-yl)methine-N-benzylamine)]-1H-indole derivatives: Synthesis, anti-HIV activity and molecular docking studies","authors":"Mashaole T.C. Ragedi ,&nbsp;Darian Naidu ,&nbsp;Oluwatoba E. Oyeneyin ,&nbsp;Nompumelelo P. Mkhwanazi ,&nbsp;Matshawandile Tukulula","doi":"10.1016/j.ejmech.2025.118301","DOIUrl":"10.1016/j.ejmech.2025.118301","url":null,"abstract":"<div><div>In this study, we report a one-pot Ugi four-component synthesis of a new series of drug-like 3-[(tetrazol-5-yl)methine-<em>N</em>-benzylamine)]-1<em>H</em>-indoles (<strong>10a-p</strong>) that target the HIV attachment and reverse transcription stages. Ten compounds (<strong>10b-c</strong>, <strong>10e</strong>, <strong>10i-j</strong> and <strong>10l-p</strong>) exhibited potent antiviral efficacy, with IC₅₀ values ranging from 0.0106 μM to 19.2 μM, and were noncytotoxic (CC₅₀ values &gt; 100 μM). Specifically, <strong>10e</strong> (IC₅₀ = 39 ± 5 nM), <strong>10i</strong> (IC₅₀ = 10.6 ± 0.1 nM) and <strong>10n</strong> (IC₅₀ = 88 ± 7.5 nM) were more active than the control drug, azidothymidine (AZT), with <strong>10e</strong> and <strong>10i</strong> showing 2.3- and 8.3-fold superior activity, respectively. Compounds <strong>10i</strong> and <strong>10o</strong> displayed activities in the early stages of viral infection in the time of addition studies, with the strongest inhibition occurring between 1 and 3 h (coinciding with the viral attachment) and moderate inhibition from 3 to 6 h (coinciding with the reverse transcription (RT)), suggesting a potential dual inhibitory activity against two critical viral stages. Following confirmatory assays, compounds <strong>10i</strong> and <strong>10o</strong> strongly inhibited HIV viral entry in the gp120 assay, while showing weak to moderate inhibition of reverse transcription in the HIV RT assay. Both compounds showed moderate to no inhibitory activity against RT mutant viruses (V241I, I257V, P272K and E297K), but maintained their activities against the wild-type virus. Molecular docking and dynamic simulations elucidated the putative binding modes and delineated critical interactions with amino acid residues, such as TRP427, GLY473, ASP368, LYS101, TY181 and TRP229. This study establishes these indole-tetrazole-based compounds as promising dual viral attachment and reverse transcriptase inhibitors, providing valuable starting points for further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118301"},"PeriodicalIF":5.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360005","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":"Discovery and optimization of potent covalent threonine tyrosine kinase (TTK) inhibitors for the treatment of triple-negative breast cancer","authors":"Cuihua Jiang ,&nbsp;Ke Chen ,&nbsp;Dongchang Li ,&nbsp;Shihe Hu ,&nbsp;Qiaomei Jin","doi":"10.1016/j.ejmech.2025.118271","DOIUrl":"10.1016/j.ejmech.2025.118271","url":null,"abstract":"<div><div>Threonine tyrosine kinase (TTK) plays a crucial element of the mitotic checkpoint, making it an attractive target for cancer therapy. With the resurgence of interest in irreversible inhibitors and identifying promising scaffolds as starting points for the development of high-quality TTK chemical probes, efforts have been directed to the discovery of irreversible TTK inhibitors. Herein, we utilized a hinge-binding scaffold hopping strategy to design new irreversible TTK inhibitors. Starting from compound <strong>I-1</strong>, a class of pyrazolo[1,5-<em>a</em>]pyrimidine pyrimidine based covalent TTK inhibitors was synthesized and evaluated. Compared with <strong>I-1</strong>, compound <strong>19</strong> exhibited exceptional TTK inhibition (IC₅₀ = 8.918 nM), substantially improved kinase selectivity, and potent antiproliferative effects against A2780 cells and MDA-MB-231 cells. Pharmacokinetic studies revealed that orally dosed <strong>19</strong> at 10 mg/kg resulted in a oral bioavailability of 26.2 %. Mechanistic studies indicated that <strong>19</strong> could covalently bind to the TTK kinase. Furthermore, <strong>19</strong> demonstrated potently anticancer efficacy in MDA-MB-231 and A2780 xenograft mouse models without obvious changes in body weight. Nevertheless, <strong>19</strong> has the potential for further optimization and is a promising anticancer drug candidate.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118271"},"PeriodicalIF":5.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360585","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":"Natural products harboring Michael receptors: A focus on targeting cancer stem cells","authors":"Shuangwei Liu ,&nbsp;Ziyu Han ,&nbsp;Zelin Xu ,&nbsp;Meichen Zhou ,&nbsp;Kun Zhang ,&nbsp;Chunfeng Xie ,&nbsp;Ning Liu ,&nbsp;Cheng Yang ,&nbsp;Jiefu Wang ,&nbsp;Guang Yang","doi":"10.1016/j.ejmech.2025.118280","DOIUrl":"10.1016/j.ejmech.2025.118280","url":null,"abstract":"<div><div>Cancer stem cells (CSCs) have been demonstrated to have a close association with cancer initiation, metastasis, drug resistance, and recurrence. Consequently, the exploration and identification of new compounds that target CSCs have become a prominent area in recent drug development. Natural products, characterized by their structural and bioactive variety, offer substantial inspiration for drug design and development. From an innovative vantage point of structure - activity relationship (SAR) investigations, this paper comprehensively reviews various categories of anti-CSCs natural products, all of which share Michael acceptors as a common pharmacophore. This review not only furnishes fresh perspectives for the research on anti-CSCs natural products but also presents alternative strategies for the molecular design and structural modification of potential drug molecules aimed at CSCs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118280"},"PeriodicalIF":5.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360577","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":"Synthesis of mitochondria-targeted caffeic acid-coumarin fluorescent conjugates to ameliorate inflammation in acute lung injury by protecting mitochondria","authors":"Yichuan Ran,&nbsp;Yongfu Wang,&nbsp;Chunwei Lv,&nbsp;Yue Zhao,&nbsp;Lifang Zheng","doi":"10.1016/j.ejmech.2025.118281","DOIUrl":"10.1016/j.ejmech.2025.118281","url":null,"abstract":"<div><div>Antioxidant supplementation demonstrates significant efficacy in alleviating lung inflammation. Herein, the mitochondria-targeted caffeic acid derivatives were designed and synthesized, aimed to improve the symptoms of acute lung injury. By conjugating phenylacrylic acid skeleton with the fluorophore carrier of coumarin-3-carboxamide using ethylenediamine link, fifteen target compounds were obtained. The structure-activity relationships and calculations of Mulliken charges revealed that the installment of electron-withdrawing groups in the α-position of olefinic bond enhanced anti-inflammatory activity. The potential compound <strong>5d</strong> containing a catechol fragment and CF₃ group on olefinic bond displayed the highest activities in suppressing the levels of inflammatory factors (NO, TNF-α, IL-6) and attenuating the carrageenan-induced paw edema in rats. Moreover, it localized in mitochondria and protected mitochondria from oxidative and inflammatory insults, including suppressing reactive oxygen species (ROS) level, inhibiting mitochondrial membrane potential collapsing and mitochondrial fragmentation, even enhancing mitophagy and inhibiting NLRP3 inflammasome activation. In vivo, it significantly attenuated lipopolysaccharide-induced acute lung injury. Our study provides evidence that protection mitochondria by phenolic antioxidant will be a promising approach to relieve inflammation response in the lung.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118281"},"PeriodicalIF":5.9,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360003","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":"Marine-derived natural products as anti-osteoporosis agents","authors":"Qianjing Zheng ,&nbsp;Salman Khan ,&nbsp;Jinchang Li ,&nbsp;Tingting Wang","doi":"10.1016/j.ejmech.2025.118284","DOIUrl":"10.1016/j.ejmech.2025.118284","url":null,"abstract":"<div><div>Osteoporosis is a prevalent global disease that imposes a significant burden on public health. Marine ecosystems, rich in natural resources, have provided a wide variety of natural products, many of which show promising potential to combat bone resorption and promote bone formation. This review systematically summarizes 152 marine-derived natural products with anti-osteoporotic activity, predominantly polyketides and terpenoids sourced from marine fungi, and elucidates their biosynthetic pathways and total synthesis strategies to accelerate the development of osteoporosis therapeutics. The review also discusses the key challenges associated with translating anti-osteoporotic natural products from lead compounds discovery into commercial development, and proposes emerging technologies such as genome mining and synthetic biology as promising strategies to overcome these barriers. By integrating advanced biotechnological advancements, this work aims to facilitate the translation of marine-derived compounds into clinically viable osteoporosis treatments. This paper highlights the foundation for future exploration of marine-derived compounds with anti-osteoporosis activity and underscores the importance of a multidisciplinary approach in addressing therapeutic needs for osteoporosis treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118284"},"PeriodicalIF":5.9,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360576","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":"Discovery of an asymmetric triphenylamine-based onium salt as a G-quadruplex-targeted fluorescent ligand for potential triple-negative breast cancer treatment","authors":"Yun Dong ,&nbsp;Ming-Hao Hu","doi":"10.1016/j.ejmech.2025.118292","DOIUrl":"10.1016/j.ejmech.2025.118292","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive nature and lack of targeted receptors. This study introduced <strong>IMB</strong>, an asymmetric triphenylamine-based onium salt, as a novel mitochondrial G-quadruplex (mtG4)-targeted photosensitizer for photodynamic therapy (PDT). <strong>IMB</strong> demonstrated selective mitochondrial accumulation and strong mtG4-binding affinity, rendering it as a promising mtG4 fluorescent probe with near infrared (NIR) properties. Moreover, under white-light irradiation, the mtG4-bound <strong>IMB</strong> generated potent Type-I ROS, which may accelerate mtDNA damage, induce mitochondrial dysfunctions, leading to cell cycle arrest, and apoptosis. Functional assays revealed its potent antiproliferative effects, showing inhibition in cell migration, colony formation, and 3D spheroid growth. These findings established mtG4-targeted PDT as a promising strategy for TNBC, with <strong>IMB</strong> serving as a lead candidate for further preclinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118292"},"PeriodicalIF":5.9,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360671","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":"Piperidine-containing drugs and recently studied analogs – biological activity, mechanism of action and synthetic cascade access to their scaffolds","authors":"Daniel Łowicki,&nbsp;Piotr Przybylski","doi":"10.1016/j.ejmech.2025.118213","DOIUrl":"10.1016/j.ejmech.2025.118213","url":null,"abstract":"<div><div>This review provides a comprehensive summary of currently marketed piperidine-containing pharmaceuticals, newly reported bioactive molecules (from 2018 to 2024), and recent advances in domino synthetic strategies focused on the last 7 years. Role of piperidine substitution patterns in modulating biological activity, pharmacokinetics, and molecular recognition (x-ray and cryo-EM structures of drug–target complexes) is discussed. Piperidine is a highly privileged scaffold in medicinal chemistry, present in a wide range of clinically approved drugs and lead compounds, mainly active against cancer, CNS and infective diseases, except for antiviral agents. The piperidine is relatively universal structural motif which offers often relatively high chemical stability, modulation of lipophilicity <em>vs.</em> water solubility, H-bond donor <em>vs.</em> H-bond acceptor properties, or adaptation (<em>via</em> conformation changes) the shape of molecule to steric demands of binding pockets of molecular targets, i.e. crucial physicochemical parameters of considered drugs. From the biological perspective the presence of piperidine motif in structure enhances druggability as this heterocycle is relatively metabolically stable, facilitates drug transport through the natural membranes, improves pharmacokinetic (ADME) properties at often reduced toxicity. Metabolic stability of piperidine scaffold strongly depends on the functionalization at neighboring positions regarding the nitrogen. Hence in order to improve this parameter, using piperidine spirocyclic bioisosteres or spiro-piperidyl systems is often recommended. It is interesting that prodrug but not adjuvant strategy is used to design piperidine-containing drugs. In the synthetic section, green cascade transformations are discussed with complete mechanistic interpretations, including a critical evaluation of proposed pathways and suggestions for more accurate mechanistic alternatives.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118213"},"PeriodicalIF":5.9,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342345","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 novel 1,2,4-triazole derivative inhibits epithelial-mesenchymal transition in metastatic colorectal cancer via β-catenin suppression","authors":"Heba Abdelmegeed ,&nbsp;Heba Abo-Salem ,&nbsp;Hayam A. Abd El Salam ,&nbsp;Eslam R. El-Sawy","doi":"10.1016/j.ejmech.2025.118279","DOIUrl":"10.1016/j.ejmech.2025.118279","url":null,"abstract":"<div><div>1,2,4-Triazole derivatives have emerged as a significant class of compounds with diverse biological activities, notably their anticancer properties. This therapeutic utility lies in their molecular flexibility and their capacity to interact with key enzymes implicated in oncogenesis. However, their role in inhibiting tumor cell metastasis is not fully investigated. Hence, we assessed the ability of a series of 5-heptadecyl-4H-1,2,4-triazole incorporated N-substituted indoles, which we previously developed, to suppress the migration of metastatic colorectal cancer. To achieve that, we analyzed the mechanism underlying the antitumor effect of compound <strong>10d</strong>, which demonstrated the highest antitumor activity among the synthesized 1,2,4-triazole/indole hybrids. Furthermore, we investigated the potential of compound <strong>10d</strong> to inhibit epithelial-mesenchymal transition (EMT) in colorectal cancer cells. Our findings showed that compound <strong>10d</strong> exerts its antitumor action by inducing both apoptosis and cell cycle arrest at S-phase. Moreover, <strong>10d</strong> inhibited the migration and invasion of colorectal cancer cells in vitro, in addition to EMT inhibition. This inhibition was attributed to its capacity to suppress the transcription of β-catenin and vimentin, which are key markers of EMT. Additionally, <strong>10d</strong> significantly inhibited β-catenin at the protein level. Collectively, our findings highlight the promising potential of <strong>10d</strong> as a novel therapeutic agent for reducing cell migration and invasion, thereby inhibiting colorectal cancer metastasis. Molecular docking study supported the results for compound <strong>10d</strong>. Where <strong>10d</strong> showed strong binding affinity to a human β-catenin complex (PDB ID: <span><span>2GL7</span><svg><path></path></svg></span>) (−6.5 kcal/mol) via hydrogen bonds and hydrophobic interactions, along with specific drug-likeness properties, including favorable oral absorption, moderate solubility, and a safer toxicity profile, despite some metabolic limitations.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118279"},"PeriodicalIF":5.9,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360672","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":"Identification of a novel PDE4 inhibitor inspired by leoligin-derived lignans","authors":"Christine Coffey ,&nbsp;Alexander F. Perhal ,&nbsp;Wito Richter ,&nbsp;Ya Chen ,&nbsp;Thomas Linder ,&nbsp;Stefan Schwaiger ,&nbsp;Marko D. Mihovilovic ,&nbsp;Johannes Kirchmair ,&nbsp;Michael Schnürch ,&nbsp;Verena M. Dirsch","doi":"10.1016/j.ejmech.2025.118285","DOIUrl":"10.1016/j.ejmech.2025.118285","url":null,"abstract":"<div><div>The phosphodiesterase 4 (PDE4) family comprises isoenzymes that selectively hydrolyse the second messenger cyclic adenosine monophosphate (cAMP). PDE4s are widely expressed and play key roles in various physiologic paradigms, including immune responses, memory, cognition, and metabolism. Marketed PDE4 inhibitors, such as roflumilast and apremilast, treat chronic obstructive pulmonary disease and psoriasis. Identification and characterisation of PDE4 inhibitors offer a promising strategy for targeting diverse pathological processes. In this study, leoligin, a natural lignan found in the roots of Edelweiss (<em>Leontopodium nivale</em> subsp. <em>alpinum</em> (Cass.) Greuter (Asteraceae)) and 165 analogues were screened for their PDE inhibitory activity using a cAMP accumulation assay employing an exchange protein activated by cAMP-based biosensor. Six compounds, including leoligin itself, were identified to cause a significant accumulation of cAMP, and structure-activity relationships were deduced. One analogue, designated <em>LT-104A</em>, showed a concentration-dependent activity with the highest determined potency (EC₅₀ = 1.9 μM) in the cAMP accumulation assay. <em>LT-104A</em> was further characterised using a CRE-Luciferase assay, showing comparable activity to known PDE4 inhibitors in inducing the anti-inflammatory cAMP-PKA-CREB pathway. The inhibitory activity of <em>LT-104A</em> was also confirmed against recombinant PDE4D3 in a cell-free cAMP hydrolysis assay (IC₅₀ = 9.3 μM). The potential binding mode of <em>LT-104A</em> with the catalytic domain of PDE4D was predicted using induced-fit docking. Lastly, a functional study was conducted in LPS-activated macrophages, where <em>LT-104A</em> reduced nitric oxide release and decreased mRNA expression of <em>Il1b</em> and <em>Nos2</em>. In conclusion, extensive in vitro screening of leoligin analogues led to the identification and characterisation of a novel PDE4 inhibitor, <em>LT-104A</em>, with potential in vitro anti-inflammatory properties.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118285"},"PeriodicalIF":5.9,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342420","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":"Polymerase theta (Polθ) and cancer: Role in tumor progression and potential as a therapeutic target","authors":"Yueqi Zuo ,&nbsp;Ke Zhang ,&nbsp;Mengchi Zhang ,&nbsp;Ting Wang ,&nbsp;Yongxia Zhu ,&nbsp;Ningyu Wang ,&nbsp;Xingchun Gou","doi":"10.1016/j.ejmech.2025.118283","DOIUrl":"10.1016/j.ejmech.2025.118283","url":null,"abstract":"<div><div>DNA double-strand breaks (DSBs) are a severe form of DNA damage that can lead to large chromosomal deletions, gene inactivation, genomic rearrangements, and cell death. Cellular repair pathways are vital for maintaining genomic stability and integrity, both of which are essential for cell growth and development. Recent studies highlight that DNA polymerase theta (Polθ) is a promising target in cancer research, as inhibiting Polθ is synthetically lethal in the context of homologous recombination (HR) deficiencies, such as mutations in the breast cancer susceptibility genes <em>BRCA1</em> and <em>BRCA2</em>. Exploring the relationship between Polθ and cancer may offer new therapeutic strategies. This review outlines the mechanisms of DSB repair pathways, with a focus on the role of Polθ in polymerase theta-mediated end-joining (TMEJ). We also discuss the structure and biological functions of Polθ, emphasizing the synthetic lethal interactions between Polθ and various DNA repair genes in cancer therapy. Furthermore, we examine the types and therapeutic effects of Polθ inhibitors in tumor treatment, as well as their clinical applications and challenges. Although further research is required to resolve challenges in clinical applications, investigating Polθ inhibitors as targeted therapies could have implications for anticancer therapies, particularly in HR-deficient cancers.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118283"},"PeriodicalIF":5.9,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314711","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}