Bioorganic & Medicinal Chemistry最新文献

{"title":"Targeting epithelial-mesenchymal transition and apoptosis: novel histone methyltransferase inhibitors for colon cancer suppression","authors":"Hsueh-Yun Lee ,&nbsp;Chia-Hsuan Chang ,&nbsp;Yi-Ting Liu ,&nbsp;Deepa Rohidas Landge ,&nbsp;Tzu-Ying Chen ,&nbsp;Er-Chieh Cho","doi":"10.1016/j.bmc.2026.118570","DOIUrl":"10.1016/j.bmc.2026.118570","url":null,"abstract":"<div><div>Colon cancer is one of the major causes of cancer-related death worldwide and is considered a consequence of the accumulation of genetic and epigenetic changes in normal cells. Among epigenetic modifications, the critical involvement of histone methyltransferase (HMT) in epigenetic alterations and tumorigenesis has been widely reported. Targeting HMTs as an anti-cancer strategy has attracted considerable attention; however, limited HMT inhibitors have achieved success in the field of clinical oncology.</div><div>In this study, we aimed to design and synthesize small molecular compounds as potential HMT inhibitors for cancer therapy, and to investigate their biological impacts on cancer cell lines. We examined the anti-proliferative effect of potential HMT inhibitors in multiple cancer cell lines. Among all candidates, two 1-benzylpiperidin-4-amine derivatives, DHT-07343 and DHT-07171, exhibited the most significant anti-cancer potential, especially in colon cancer cells. These two compounds could suppress methyltransferase activity, likely via regulating nuclear receptor-binding SET domain protein 1 (NSD1) and NSD2. In addition, these two compounds were able to inhibit cancer cell migration and regulate epithelial-mesenchymal transition (EMT) markers. Treatment of these two compounds led to apoptosis induction as well as cell cycle regulation. Finally, non-cancerous human cell lines and the zebrafish embryotoxicity model were utilized for the evaluation of the drug safety of DHT-07343 and DHT-07171.</div><div>In conclusion, our study demonstrated that DHT-07343 and DHT-07171 could be promising HMT inhibitors that exhibit anti-cancer activities by suppressing cell proliferation and migration, providing a potential strategy for colon cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118570"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing N-substituted benzotriazole scaffolds as potent methionine aminopeptidase inhibitors: from chemical design to cellular efficacy","authors":"Vivekananda Saha ,&nbsp;Ajinur Hossain ,&nbsp;Khairud Zaman Miraj ,&nbsp;Nasim Sepay ,&nbsp;Souvik Sarkar ,&nbsp;Subarna Roy ,&nbsp;Jungkyun Im ,&nbsp;Goutam Biswas","doi":"10.1016/j.bmc.2026.118553","DOIUrl":"10.1016/j.bmc.2026.118553","url":null,"abstract":"<div><div>Herein, we present the synthesis, characterization, and biological evaluation of twenty-five N-substituted benzotriazole derivatives as potential anticancer agents targeting methionine aminopeptidase (MAP) enzymes. The compounds were synthesized following a conventional procedure and characterized by spectroscopic techniques, including ¹H and ¹³C NMR, FT-IR, and LCMS, for structural endorsement. Molecular docking and dynamics simulations over 100 ns revealed strong binding affinities and stable complex formation between several N-substituted benzotriazole derivatives and MAP type-I, outperforming the reference anticancer drugs in key protein-ligand interactions. Additionally, the compound <strong>4g</strong> showed the highest Mechanics Poisson-Boltzmann Surface Area (MMPBSA) energy of −12.53 ± 4.3 kcal/mol, with a major contribution from TYR-196 and TRP-353 amino acid residues. Pharmacokinetic profiling using ADMET tools showed that most compounds possessed favorable drug-like properties, suitable absorption, and low toxicity. Biological assays demonstrated significant cytotoxicity, with an IC₅₀ value of 34.8 μM for <strong>4g</strong>. The relative apoptotic rates of HeLa cancer cell lines using selected derivatives against the control showed notable therapeutic outcomes for <strong>4g</strong>, <strong>6d</strong>, and <strong>6f</strong>. In summary, this integrated approach highlights N-substituted benzotriazole scaffolds as promising modular precursors for the development of targeted anticancer therapies focused on metabolic enzyme inhibition.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118553"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and anti-tumor activities of pyridine-benzamide containing dithiocarbamate moiety as EZH2 inhibitors","authors":"Hui Lu,&nbsp;Yuling Xiang,&nbsp;Ping Gong","doi":"10.1016/j.bmc.2025.118514","DOIUrl":"10.1016/j.bmc.2025.118514","url":null,"abstract":"<div><div>Based on the reported Enhancer of zeste homolog 2 (EZH2) inhibitors characterized by pyridone-benzamide components, a series of derivatives were designed and synthesized through structural optimization based on rational drug design principles. Compound <strong>N16</strong> demonstrates significant inhibitory effects on EZH2 WT, with an IC₅₀ of 0.3 nM. Furthermore, compound <strong>N16</strong> effectively inhibited the proliferation of Pfeiffer cells (IC₅₀ = 0.0074 ± 0.002 μM) and demonstrated greater efficacy compared to Tazemetostat. Compound <strong>N16</strong> induced apoptosis in Pfeiffer cells and caused cell cycle arrest in the G1 phase. After treatment of Pfeiffer cells with <strong>N16</strong> for 48 h at the indicated concentrations (1.85, 3.70, 7.40, 14.8 and 29.60 nM), the percentage of Pfeiffer cells in the G1 phase increased from 88.75 % (in the control group) to 85.2, 96.61, 92.04, 93.35 and 91.05 %, respectively. The author employed Western blotting analysis to examine the effect of compound <strong>N16</strong> on H3K27 methylation. The results significantly showed that under high-concentration conditions, compound <strong>N16</strong> obviously inhibited the trimethylation of lysine 27 on histone H3 (H3K27me3) in Pfeiffer cells. Our findings suggest that <strong>N16</strong> is a promising EZH2 inhibitor, and further investigation is warranted to validate these findings and facilitate the subsequent development of <strong>N16</strong>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118514"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategic approaches to the discovery of biologically active indole derivatives: a comprehensive review","authors":"Gui-Ping Gao ,&nbsp;Quan-Ke Li ,&nbsp;Jin-Cheng Ma ,&nbsp;Zhi-Jun Zhang ,&nbsp;Shao-Yong Zhang ,&nbsp;Ying-Qian Liu","doi":"10.1016/j.bmc.2025.118541","DOIUrl":"10.1016/j.bmc.2025.118541","url":null,"abstract":"<div><div>Indole, an aromatic heterocyclic compound formed by the fusion of a benzene ring with a pyrrole ring, is widely distributed in the secondary metabolites of plants, animals, and marine organisms. Owing to its unique physicochemical properties and high structural modifiability, indole derivatives can engage in specific interactions with various biological targets, demonstrating a broad spectrum of bioactivities including anticancer, anti-inflammatory, antiviral, and antibacterial effects. Consequently, indole holds an indispensable position in innovative drug discovery and development. This review provides a comprehensive summary of the primary strategies employed in the discovery of indole derivatives. These encompass structure optimization approaches inspired by natural products, such as structure simplification, diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS), the “pseudo-natural product” (PNP) strategy, and bioinspired synthesis based on biosynthetic building blocks. Additionally, strategies like scaffold hopping, molecular hybridization, drug repurposing, and multicomponent reactions (MCRs) for constructing indole-based molecules are discussed. Particular emphasis is placed on target structure-based discovery strategies for indole derivatives, including ligand-based structure modification, molecular docking-assisted high-throughput virtual screening, and fragment-based drug design (FBDD). Furthermore, the application of emerging techniques such as phenotypic screening, DNA-encoded library (DEL) technology, and free energy perturbation (FEP) calculations in indole-based drug research and development is highlighted. This review aims to systematically organize the multi-dimensional R&amp;D framework for indole derivatives, analyze the specific value of each strategy in addressing drug discovery challenges, and provide a theoretical foundation and methodological support for the rational design and development of novel indole-based drugs. It is anticipated that this work will further enhance the efficiency and innovation level in the development of this class of compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118541"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regio- and Diastereoselective Arylation of rosin acids: A practical strategy for bioactive compounds discovery","authors":"Farked S. Wahoodi ,&nbsp;Antonio Fernández ,&nbsp;Juan Sainz ,&nbsp;Fernando Rodríguez-Serrano ,&nbsp;Fernando J. Reyes-Zurita ,&nbsp;Rachid Chahboun","doi":"10.1016/j.bmc.2026.118554","DOIUrl":"10.1016/j.bmc.2026.118554","url":null,"abstract":"<div><div>A mild, sustainable, and cost-effective arylation of rosin-acids is reported. This new approach, based on a regio- and diastereoselective Friedel-crafts alkylation, enabled the synthesis of fourteen new resin acid derivatives. Selected compounds were screened for cytotoxic activity against three human tumor cell lines. Remarkably, quinone <strong>14</strong> exhibited significant activity: Against HL-60 cells (IC₅₀ = 5.94 <span>μ</span>M) cell, and phenol <strong>11f</strong> displayed selective cytotoxic activity against HT-29 cells (IC₅₀ = 8.90 <span>μ</span>M) cells. Flow cytometry confirmed apoptosis as the primary mechanism of cell death, reaching 78% in HL-60 (<strong>14</strong>) and 72.6% in HT-29 (<strong>11 g</strong>), with minimal necrosis. Cell-cycle analysis showed S-phase arrest in HL-60 (<strong>14</strong>) and G₀/G₁ arrest in HT-29 (<strong>11f</strong>/<strong>11 g</strong>). Consistently, ΔΨm assays showed near-complete collapse in HL-60 (<strong>14</strong>) and significant depolarization in HT-29 (<strong>11 g</strong>). In addition, the anti-inflammatory activity of some synthesized compounds was assessed in LPS-stimulated RAW 264.7 macrophages. All tested compounds achieved 70–100% NO inhibition at subcytotoxic concentrations. Derivatives <strong>13</strong> and <strong>14</strong> showed the highest activity (IC_{50 NO} = 0.85 μM and 5.43 μM, respectively). Overall, this green arylation approach enables rapid access to 7-aryl methyl ester dehydroabietic acid libraries with significant cytotoxic and anti-inflammatory activities</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118554"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and characterization of a high-affinity G-quadruplex binding peptide via mRNA display","authors":"Naka Kudo Ida ,&nbsp;Yoshimasa Kawaguchi ,&nbsp;Shiroh Futaki ,&nbsp;Miki Imanishi","doi":"10.1016/j.bmc.2025.118543","DOIUrl":"10.1016/j.bmc.2025.118543","url":null,"abstract":"<div><div>G-quadruplexes (G4s) are non-canonical secondary structures of nucleic acids that play crucial roles in gene expression, and their dysregulation has been implicated in various diseases. Therefore, development of G4-binding molecules, including peptides and proteins, is required to modulate G4-dependent biological processes for therapeutic purposes. In this study, a novel G4-binding peptide with high affinity for the G4 structure was developed using directed evolution based on mRNA display. The identified peptide, <strong>LP7</strong>, exhibited a preferential affinity for parallel G4 structures. Dimerization of <strong>LP7</strong> significantly enhanced its binding to hTERC rG4 by approximately 70-fold, with a <em>K</em>_d of 7 nM. Analysis of the sequence-activity relationship revealed that both the basic and aromatic amino acid residues of the peptide are critical for its binding affinity to G4. Functional assays confirmed that <strong>LP7</strong> inhibits reverse transcription in a G4-dependent manner by binding to the rG4 region. This study demonstrates the successful application of the mRNA display platform for discovering novel G4-binding peptides. A detailed characterization of <strong>LP7</strong> provides valuable insights into the molecular interactions that govern G4 recognition. These findings highlight the potential of G4-binding peptides as tools for targeting and regulating G4-mediated gene functions, offering a promising avenue for the development of G4-dependent therapeutic strategies in the future.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118543"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and evaluation of 5-phenoxylmethyl-1,3,4-oxadiazol-2-ones/oxadiazole-2-thiones as potent urease inhibitors","authors":"Meng-Jing Xiao ,&nbsp;Yi-Ning Wang ,&nbsp;Liang-Chao Yuan ,&nbsp;Yao Zeng ,&nbsp;Zi-Wei Wu ,&nbsp;Yun-Qi Zhang ,&nbsp;Zhu-Ping Xiao ,&nbsp;Hai-Liang Zhu","doi":"10.1016/j.bmc.2026.118567","DOIUrl":"10.1016/j.bmc.2026.118567","url":null,"abstract":"<div><div>A serial of oxadiazol-2-ones/oxadiazole-2-thiones were designed, synthesized and evaluated as urease inhibitors. Out of these compounds, oxadiazole-2-thiones showed excellent inhibition against urease with twenty-two showing higher potency than the clinical used drug AHA. It is emphasized that 1,3,4-oxadiazole-2-thiones containing 3-propylphenoxy (d34) and 3-nitrophenoxy (d46) on the side chain were the two most active compounds. They were demonstrated having 230- and 360-fold higher potency than AHA and inhibiting urease with a mixed mechanism.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118567"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiazolidinedione-based dual inhibitors of α-amylase and aldose reductase: Design, in vitro evaluation, and in vivo hypoglycemic activity","authors":"Mohammad M. Al-Sanea ,&nbsp;Mohamed R. Elnagar ,&nbsp;Ahmed A.B. Mohamed ,&nbsp;Hamed W. El-Shafey ,&nbsp;Lamiaa O. El-Halaby ,&nbsp;Samar S. Tawfik ,&nbsp;Susi Zara ,&nbsp;Marwa Balaha ,&nbsp;Abdullah A. Elgazar ,&nbsp;Syed N.A. Bukhari ,&nbsp;Abdelrahman Hamdi","doi":"10.1016/j.bmc.2026.118569","DOIUrl":"10.1016/j.bmc.2026.118569","url":null,"abstract":"<div><div>This study reports the design, synthesis, and biological evaluation of thiazolidinedione (TZD) derivatives as dual inhibitors of α-amylase (α-AMY) and aldose reductase (AR) for potential use in the management of diabetes mellitus. Using a structure-based design strategy, the epalrestat scaffold was modified by introducing a TZD core with either an <em>N</em>-ethyl urea or <em>N</em>-acetamide linker and various benzylidene substituents. Two series of compounds (<strong>8a–g</strong> and <strong>9a–g</strong>) were synthesized and characterized. <em>In vitro</em> assays showed that several derivatives exhibited dual inhibitory activity. Compound <strong>9a</strong>, containing an <em>N</em>-acetamide linker and a 4-fluorobenzylidene group, inhibited AR (IC₅₀ = 117.6 nM) and α-AMY (IC₅₀ = 2.2 μM), with lower IC₅₀ values than epalrestat (127 nM) and acarbose (15 μM), respectively. Structure–activity relationship analysis indicated that the <em>N</em>-acetamide linker favored AR inhibition, whereas the <em>N</em>-ethyl urea linker was more favorable for α-AMY inhibition. Kinetic studies showed that <strong>9a</strong> inhibits AR non-competitively and α-AMY <em>via</em> a mixed-type mechanism. Molecular docking suggested that <strong>9a</strong> binds to an allosteric site in AR and the catalytic pocket of α-AMY. In a streptozotocin-induced diabetic mouse model, <strong>9a</strong> reduced blood glucose levels by 68.4% at a dose of 50 mg/kg. These results suggest that <strong>9a</strong> could serve as a starting point for further development of multi-target antidiabetic agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118569"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bio-responsive self-assembled nanoparticles of fatty acid prodrugs of sulfapyridine for the management of Rheumatoid arthritis","authors":"Pooja Rani ,&nbsp;Monica Gulati ,&nbsp;Bhupinder Kapoor","doi":"10.1016/j.bmc.2026.118577","DOIUrl":"10.1016/j.bmc.2026.118577","url":null,"abstract":"<div><div>Despite significant advancements in medical research, the treatment of rheumatoid arthritis (RA) is still challenging due to limitations associated with the conventional therapies, which include low tissue specificity, poor retention within inflamed joints, and systemic toxicity. Sulfapyridine (SP), a second-line drug for the management of RA, has low solubility and permeability, classifying is as a BCS class IV drug. To overcome these limitations, SP was chemically conjugated with fatty acid (FA) side chains to make amphiphilic prodrugs that formed nanostructures on self-assembly in aqueous milieu. Among the synthesized prodrugs, heptanoyl and oleoyl derivates <em>i.e.</em>, SP-Hept and SP-Ole were selected as lead candidates for further pharmacological evaluation due to their favorable self-assembly behaviour and physicochemical properties. Both prodrugs spontaneously formed uniform sized spherical nanoparticles (NPs) with high colloidal stability, which was better maintained under refrigerated storage. <em>In vitro</em> cytotoxicity studies using L929 fibroblast cells demonstrated reduced toxicity for the prodrugs compared to the parent drug. Controlled and selective release of SP was confirmed <em>via</em> pH- and enzyme-responsive hydrolysis in chemical buffers, human plasma, synovial fluid, and simulated synovial fluid (SSF)., notably, SP-Hept showed greater sensitivity to acidic conditions and esterase activity, whereas SP-Ole was preferentially cleaved by collagenase. In a complete Freund's adjuvant (CFA)-induced rat arthritis models, treatment with these NPs significantly alleviated paw swelling and joint inflammation by downregulating inflammatory mediators. Histological and radiographic analyses confirmed preservation of joint architecture and cartilage integrity, while hematological and biochemical parameters were restored toward normal levels. Overall, these findings highlight the potential of SP-Hept and SP-Ole NPs as a precisely tunable, localized drug delivery platform for improved RA management.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118577"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors","authors":"Lu Han ,&nbsp;Shumin Zang ,&nbsp;Wenxin Li ,&nbsp;Hangtian Yue ,&nbsp;Xiaoqian Zhou ,&nbsp;Jie Chen ,&nbsp;Meiyu Geng ,&nbsp;Wenhu Duan ,&nbsp;Zuoquan Xie ,&nbsp;Zhengsheng Zhan","doi":"10.1016/j.bmc.2026.118571","DOIUrl":"10.1016/j.bmc.2026.118571","url":null,"abstract":"<div><div>The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-<em>b</em>][1,4]thiazin-2(3<em>H</em>)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound <strong>11 h</strong> as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC₅₀ of 8.8 or 11.5 nM. Compound <strong>11 h</strong> markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, <strong>11 h</strong> achieved robust <em>in vivo</em> activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of <strong>11 h</strong>-STING indicates that <strong>11 h</strong> engages the transmembrane area of STING.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"135 ","pages":"Article 118571"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}