Bioorganic Chemistry最新文献

{"title":"Tunable triazole-based cholera toxin inhibitors: A QSAR-guided design and evaluation approach","authors":"Huma Basheer ,&nbsp;Chandra S. Azad ,&nbsp;M. Samim ,&nbsp;Imran A. Khan","doi":"10.1016/j.bioorg.2026.109563","DOIUrl":"10.1016/j.bioorg.2026.109563","url":null,"abstract":"<div><div>Cholera toxin B subunit (CTB) is a validated target for anticholera therapeutics, but current inhibitors often suffer from synthetic complexity and limited tunability. This study aimed to develop a compact, tunable triazole scaffold exhibiting low-micromolar potency combined with high synthetic tractability. We applied a unified, QSAR-driven, multiscale computational-experimental workflow integrating molecular docking, induced fit docking (IFD), molecular dynamics (MD), QM/MM calculations, and descriptor-based QSAR modeling to prioritize a focused library of 44 N-sulfonyl triazole inhibitors.</div><div>QSAR modeling employed multiple regression techniques on molecular descriptors derived from <em>E</em>-Dragon software and quantum mechanical (QM/QM-MM) parameters. Models including Ordinary Linear Regression, LASSO, Ridge, Elastic Net, Random Forest, Support Vector Machine (SVM), and Gradient Boosting Machine (GBM) were developed. The best predictive performance was achieved by SVM (test R² = 0.79, RMSE = 0.49) and Random Forest (test R² = 0.77, RMSE = 0.52) on <em>E</em>-Dragon descriptors, while multiple linear regression yielded outstanding fits on QM descriptors (test R² up to 0.98, RMSE ∼0.14). Key molecular descriptors influencing activity included hydrogen bond donor count (ndonr), polarizability (AlogP), and topological indices (Jhetv).</div><div>Guided by these QSAR models, lead candidates were synthesized <em>via</em> regioselective Cu(I)/Ru-catalyzed click chemistry, with experimental CTB-ELISA screening confirming compound <strong>5d</strong> as the most potent inhibitor (IC₅₀ = 11.78 ± 1.2 μM). Computational studies consistently supported these findings, demonstrating favorable binding energetics, dynamic adaptability, and optimal electronic complementarity for lead compounds.</div><div>This integrated strategy not only delivers a potent, synthetically accessible monovalent CTB inhibitor but also provides a rational, data-driven platform for rapid design and optimization for multivalent cholera toxin antagonists with improved efficacy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109563"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076812","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":"Development of selective NBD-based fluorescent probes for in vitro detection of factor XIa and Thrombus imaging","authors":"Xinyu Zhuang ,&nbsp;Han Yang ,&nbsp;Fengjiao Zhou ,&nbsp;Ruixing Li ,&nbsp;Xingyu Zhao ,&nbsp;Meijuan Zou ,&nbsp;Qing Li","doi":"10.1016/j.bioorg.2026.109571","DOIUrl":"10.1016/j.bioorg.2026.109571","url":null,"abstract":"<div><div>Factor XIa (FXIa) is a promising target for safer anticoagulants. Herein, a series of NBD-based fluorescent probes (<strong>FNC2–FNC6</strong>) were developed by linking an FXIa inhibitor scaffold to an NBD fluorophore via alkyl chains of varying lengths. Molecular dynamics simulations revealed that shorter linkers, especially a two‑carbon chain, stabilize NBD binding in the FXIa pocket, enhancing fluorescence. Among these probes, <strong>FNC2</strong> displayed potent FXIa inhibition (Ki = 14.2 nM) and selectivity over related proteases. It exhibited linear fluorescence increase upon FXIa binding (R² = 0.9952; LOD = 1.19 μg/mL), enabling accurate quantification in immunoglobulin products (recovery: 94.41%–103.76%; RSD &lt; 2%). <strong>FNC2</strong> visualized FXIa in human plasma clots with 2.7-fold higher signal than free NBD, suppressed dose-dependently by asundexian. This structure-guided approach yields selective probes for FXIa detection and thrombus imaging.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109571"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099842","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":"NIR-triggered synergistic Photothermal therapy and type I photodynamic therapy using supramolecular porphyrin-Phthalocyanine assemblies for the treatment of multidrug-resistant bacterial infections","authors":"Wei Su ,&nbsp;Jiayin Chen ,&nbsp;Chenxiang Lin ,&nbsp;Jun-An Xiao ,&nbsp;Peiyuan Li","doi":"10.1016/j.bioorg.2026.109558","DOIUrl":"10.1016/j.bioorg.2026.109558","url":null,"abstract":"<div><div>Multidrug-resistant bacterial infections, such as methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), pose a severe global health threat exacerbated by the limitations of conventional antibiotics and the hypoxic microenvironment of infections. To address this, we developed a novel supramolecular photosensitizer, TAPc@TMAP, via electrostatic self-assembly of anionic 2,3,9,10,16,17,23,24-octacarboxyphthalocyanine (TAPc) and cationic 5,10,15,20-tetrakis(4-trimethylammoniophenyl) porphyrin tetraiodide (TMAP). This nanocomposite exhibits exceptional near-infrared (NIR) responsiveness at 808 nm, enabling synergistic type-I photodynamic therapy (PDT) and photothermal therapy (PTT). Under NIR irradiation, TAPc@TMAP generated superoxide radicals (O₂^•−) with 55% efficiency retention under hypoxic conditions, significantly outperforming individual components (TAPc and TMAP), and achieved a photothermal conversion efficiency of 31.9% with negligible degradation over five cycles. In vitro, TAPc@TMAP eradicated 99.69% of MRSA at 30 μM concentration under 808 nm laser radiation (0.5 W/cm², 30 min), inducing bacterial membrane rupture as confirmed by scanning electron microscopy. In a murine model of MRSA-infected wounds, TAPc@TMAP-mediated phototherapy reduced the residual wound area to 14.19 ± 1.9% within 12 days (vs. 33.11 ± 14% in controls) and decreased bacterial burden by 95.96% at day 8. Histological and immunohistochemical analyses revealed attenuated inflammation (22.65% reduction in TNF-α expression, <em>p</em> &lt; 0.001), enhanced angiogenesis (5.06% increase in CD31-positive microvessels, p &lt; 0.001), and organized collagen deposition. This study demonstrates the robust antibacterial efficacy and wound healing promotion of TAPc@TMAP via oxygen-independent type-I PDT/PTT synergy, offering a promising strategy for combating multidrug-resistant bacterial infections.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109558"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057333","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":"Recent progress of novel strategies of small molecule drugs to treat inflammatory bowel diseases","authors":"Xiaoguang Huang,&nbsp;Yijia Huang","doi":"10.1016/j.bioorg.2026.109535","DOIUrl":"10.1016/j.bioorg.2026.109535","url":null,"abstract":"<div><div>The rising incidence of inflammatory bowel disease (IBD) in developing countries over recent years has elevated this condition to a serious public health concern. The limited remission rates of existing drugs for the clinical treatment of this disease highlight the urgent need to develop safer, more effective therapeutics. This review covers recent progress in research to elucidate the novel mechanisms of action of small molecule drugs that target receptors, kinases, enzymes, and inflammasomes in immune cells. Meanwhile, the paper also summarized the biological activities of these small molecule drugs, indications in clinical trials and the progress of clinical trials. It is necessary to develop multi-target or double-target therapeutic drugs to treat IBDs in the future.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109535"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076751","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":"Visualizing and mapping Aβ plaques by curcumin-derived NIR sensors: Multitarget theranostic agents for Alzheimer's disease","authors":"Álvaro Sarabia-Vallejo ,&nbsp;José Clerigué ,&nbsp;M. Antonia Martín ,&nbsp;Pilar López-Alvarado ,&nbsp;Chongzhao Ran ,&nbsp;J. Carlos Menéndez","doi":"10.1016/j.bioorg.2026.109559","DOIUrl":"10.1016/j.bioorg.2026.109559","url":null,"abstract":"<div><div>Two curcumin derivatives, structurally related to the CRANAD family of compounds, were investigated for their theranostic properties in Alzheimer's disease. They exhibited fluorescence emission in the NIR region (650–690 nm) with a significant Stokes' shift (70–90 nm). Their affinity for Aβ aggregates, oligomers and monomers allows to detect, differentiate and map <em>in vitro</em> the various amyloid species within and around the plaques by fluorescence microscopy. Fluorescence lifetime microscopy, a robust and sensitive technique allowing to visualize biomolecules with high spatial resolution at nanomolar level, was employed to discriminate the less soluble and more toxic species from the more soluble ones by determination of fluorescence lifetime values at the core and the periphery of the β-amyloid plaques, without the need for the use of antibodies. <em>In vivo</em> brain images show that the fluorescence signals of the sensors are 5–6 times higher for transgenic mice with aberrant proteins than wild type mice after intraperitoneal injection, differentiating plaques of amyloid beta (Aβ) protein in real samples <em>in vivo</em>. These experiments also showed a good blood brain barrier penetration of the sensors, which remain in the brain for 90–120 min, opening up the possibility of their therapeutic use. <em>In vitro</em> studies showed a good activity of both compounds as inhibitors of Aβ aggregation into small soluble oligomers and large insoluble aggregates and also the inhibition of tau protein aggregation, both in a dose-dependent manner. These studies confirm that both compounds have an unprecedented profile that justifies their further study as small-molecule theranostic agents in AD.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109559"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076911","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 novel procaspase-3 activators for the targeted therapy of triple-negative breast cancer","authors":"Zhongyuan Guo ,&nbsp;Huan Liu ,&nbsp;Chenxiaoning Meng ,&nbsp;Hong Yang ,&nbsp;Xinyue Zhang ,&nbsp;Xiaoqian Liu ,&nbsp;Zhimin Wang","doi":"10.1016/j.bioorg.2026.109569","DOIUrl":"10.1016/j.bioorg.2026.109569","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) remains a formidable clinical challenge owing to its aggressive phenotype and limited treatment options. To address this, we employed ligand-based rational drug design coupled with scaffold hybridization to develop a series of novel procaspase-3 activators. From 28 designed compounds, F17 and F21 emerged as lead candidates, exhibiting superior in vitro procaspase-3 activation. Density functional theory calculations confirmed their enhanced zinc-binding affinity, with adsorption energies (Eads) of −14.8332 eV (F17) and −14.8797 eV (F21), compared to −12.7474 eV for PAC-1, along with stronger electrostatic potential minima (−67.20 and −66.99 kcal/mol, respectively). In silico ADMET profiling indicated favorable drug-like properties, including good aqueous solubility, low blood-brain barrier penetration, and moderate intestinal absorption. In TNBC MDA-MB-231 models, both compounds demonstrated potent anti-proliferative activity, with IC₅₀ values of 25.82 μM (F17) and 25.03 μM (F21) after 48 h, outperforming PAC-1 (33.81 μM). They also significantly inhibited cell migration, reducing wound closure to 11.19% (F21) compared with 20.60% in controls, and induced caspase-3-dependent apoptosis. Importantly, in vivo neurotoxicity assessments revealed no significant neuronal damage at doses up to 50 mg/kg, underscoring their improved safety profile over earlier activators. These results establish F21 as a particularly promising preclinical candidate and provide a rational framework for developing target-specific, neurotoxicity-sparing procaspase-3 activators for TNBC therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109569"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076912","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 quinazolinone and quinoline alkaloids from Peganum harmala L. inducing mitochondria-mediated apoptosis in liver cancer","authors":"Qin Zhang,&nbsp;Jin-Zheng Yu,&nbsp;Chun-Lei Yuan,&nbsp;Fan-Zhu Meng,&nbsp;Meng-Yue Yang,&nbsp;Han-Gao Yang,&nbsp;Fang-Shen Liu,&nbsp;Sheng-Ge Li,&nbsp;Ying Zhang,&nbsp;Yi-Yang Liu,&nbsp;Yan-Hui Zan,&nbsp;Da-Hong Li,&nbsp;Hui-Ming Hua","doi":"10.1016/j.bioorg.2026.109528","DOIUrl":"10.1016/j.bioorg.2026.109528","url":null,"abstract":"<div><div>Two novel alkaloids, pegaharmolinones A and B (<strong>1–2</strong>), featuring an unprecedented 6/6/5/5 tetracyclic skeleton based on a 1,4-dihydro-6<em>H</em>-pyrrolo[2′,3′:3,4]pyrrolo[2,1-<em>b</em>]quinazolin-6-one core, and nineteen undescribed alkaloids, including luotonins G–L (<strong>3–7</strong>, <strong>11</strong>) and pegaharmnolines A–K (<strong>18–22</strong>, <strong>26</strong>, <strong>29–30</strong>, <strong>33–35</strong>), as well as fourteen known analogs, were isolated from the aerial parts of <em>Peganum harmala</em>. Their structures and absolute configurations were determined through analysis of NMR, HR-ESI-MS spectroscopic data, and ECD calculations, supported by a strategy of CASE-DFT. A plausible biosynthetic pathway for <strong>1</strong> and <strong>2</strong> was proposed. The anticancer activity in vitro was evaluated using the CCK-8 method, revealing that compound <strong>22</strong> exhibited potent efficacy and high selectivity, with an IC₅₀ value of 6.49 μM and a selectivity index greater than 10. A series of bioassay suggested that <strong>22</strong> significantly suppressed the proliferation and migration of Hep G2 cells, and induced mitochondria-mediated apoptosis through both intrinsic and extrinsic pathways. Moreover, the SAR analysis of the tested active compounds provides structural modification strategies for the natural lead candidates <strong>2</strong> and <strong>22</strong>.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109528"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076914","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 thiazole-based hydroxamic acid derivative induces mitochondrial apoptosis and S-phase arrest in MCF-7 cells via DNA minor groove binding","authors":"Tanima Das ,&nbsp;Diya Ghosh ,&nbsp;Suvankar Karmakar ,&nbsp;Sunandita Bhar ,&nbsp;Kanisha Kar ,&nbsp;Palash Pandit ,&nbsp;Garima Chauhan ,&nbsp;Samiran Mondal ,&nbsp;Arpita Chandra","doi":"10.1016/j.bioorg.2025.109460","DOIUrl":"10.1016/j.bioorg.2025.109460","url":null,"abstract":"<div><div>Breast cancer remains a leading cause of cancer-related mortality in women globally. Approved chemotherapeutics, while effective, are associated with severe side effects, necessitating the development of safer, more targeted treatments. Our present study investigated the therapeutic potential of a thiazole-based hydroxamic acid derivative, <strong>1</strong>, against MCF-7 breast cancer cells.</div><div><strong>1</strong> exhibited potent cytotoxicity with an IC₅₀ of 21.18 ± 2.01 μM, comparable to the cytotoxicity of doxorubicin IC₅₀ of 18.08 ± 1.20 μM, yet demonstrated excellent selectivity with no significant cytotoxicity towards normal MCF-10A epithelial cells (62.37 ± 1.01 μM). Swiss ADME analysis confirmed its favourable drug-likeness and non-PgP substrate status. Flow cytometric analysis confirmed that <strong>1</strong> demonstrated substantial apoptotic cell death, inducing 45 % apoptosis compared to 2.62 % in the control group, by 75.8 % mitochondrial membrane depolarization and S-phase cell cycle arrest (with cell accumulation reaching 30.1 % at 24 h). Spectroscopic and computational studies inferred the minor-groove binding ability of <strong>1</strong> towards CT-DNA. Immunoblotting confirmed the DNA damage response (upregulation of γH2AX and p-ATM expression) which activated the intrinsic apoptotic pathway (upregulation of p53 and Bax/Bcl-2 ratio from 1.1 in control to 4 following treatment and cleaved caspase-7). The induction of DNA damage was also visualized by increase in the comet tail moment (<strong>1</strong> induced a tail moment of 54.75 ± 1.50 vs. 11.79 ± 2.23 for control). Subacute toxicity in BALB/c mice confirmed <strong>1</strong>'s safety, with no adverse liver, renal, biochemical or hematological effects up to 10 mg/kg. Collectively, the findings identify <strong>1</strong>'s potential as a chemotherapeutic lead agent for breast cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109460"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923541","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":"Synergistic effects of gentamicin, levofloxacin, and cefotaxime against Aeromonas salmonicida: In vitro and In vivo evaluation","authors":"Xingxiang Wang ,&nbsp;Lin Zhong ,&nbsp;Bhagyalakshmi Purushothaman ,&nbsp;Youming Zhang ,&nbsp;Qiang Tu ,&nbsp;Seenivasan Boopathi","doi":"10.1016/j.bioorg.2026.109485","DOIUrl":"10.1016/j.bioorg.2026.109485","url":null,"abstract":"<div><div>The increasing prevalence of multidrug-resistant (MDR) <em>Aeromonas salmonicida</em> (AS) threatens both animal and human health by limiting the effectiveness of conventional antibiotics. To identify effective therapeutic strategies, we evaluated the activity of gentamicin (GENTA), levofloxacin (LEV), and cefotaxime sodium (CFT) as individual treatments and in combination using zebrafish and rainbow trout infection models. <em>In vitro</em> checkerboard assays showed consistent synergistic effects in the GENTA–CFT combination, as confirmed by Combenefit analysis. <em>In vivo</em> experiments revealed that AS infection caused high mortality, inflammation, and impaired swimming performance in rainbow trout. Monotherapies with GENTA and CFT provided partial protection, whereas combination treatment significantly improved survival and reduced behavioral abnormalities and tissue pathology. Gene-expression profiling further showed that combination therapy markedly suppressed key inflammatory and immune-stress markers compared with infected controls. These findings highlight the superior protective efficacy of antibiotic combinations, particularly GENTA with CFT, in improving survival, alleviating tissue damage, and modulating host immune responses during AS infection in rainbow trout. The study underscores the potential of rational combination therapy as a strategy to overcome antimicrobial resistance, enhance treatment outcomes, and reduce the impact of pathogens on host health.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109485"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923530","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 5,7-Diazaindole-based ERK5 inhibitor induces endoplasmic reticulum stress and mitochondrial apoptosis in non-small cell lung Cancer","authors":"Binbin Tian ,&nbsp;Yunjie Li ,&nbsp;Pengyu Xue ,&nbsp;Renhao Chen ,&nbsp;Shuo Lv ,&nbsp;Luqian He ,&nbsp;Gaoyang Lin ,&nbsp;Jun Xiao ,&nbsp;Lin Long ,&nbsp;Guorui Cao ,&nbsp;Chuanlong Guo ,&nbsp;Longjiang Huang","doi":"10.1016/j.bioorg.2026.109512","DOIUrl":"10.1016/j.bioorg.2026.109512","url":null,"abstract":"<div><div>The extracellular signal-regulated kinase 5 (ERK5) signaling pathway represents a promising therapeutic target for non-small cell lung cancer (NSCLC), yet the development of potent and selective inhibitors remains a challenge. Leveraging the 5,7-diazaindole scaffold, a privileged structure in kinase inhibitor discovery, we designed, synthesized, and evaluated a novel series of derivatives as potential ERK5 inhibitors. Among them, compound <strong>I1</strong> emerged as the most potent candidate, demonstrating significant anti-proliferative activity against A549 human lung cancer cells with an IC₅₀ of 40.1 μM. Critically, an <em>in vitro</em> kinase assay confirmed that <strong>I1</strong> is a direct ERK5 inhibitor, exhibiting potent inhibition of purified ERK5 kinase activity with an IC₅₀ of 403.4 nM. Structure-activity relationship (SAR) studies underscored the critical importance of the unsaturated 1,2,3,6-tetrahydropyridine ring, the amide carbonyl group, and the N1<img>H moiety for optimal activity. Molecular docking revealed that <strong>I1</strong> binds robustly within the ERK5 ATP-binding site (PDB: <span><span>6HKM</span><svg><path></path></svg></span>), forming key hydrogen bonds with Met140, Asp138, and Asp200, and exhibiting a more favorable binding mode than its analogues. Mechanistic studies indicated that <strong>I1</strong> functions as a direct ERK5 inhibitor, suppressing both ERK5 phosphorylation and total protein expression. This ERK5 inhibition triggered a multi-modal anti-tumor mechanism, including the induction of endoplasmic reticulum stress, mitochondrial dysfunction (characterized by reactive oxygen species accumulation and loss of membrane potential), and ultimately, activation of the mitochondrial apoptotic pathway. Importantly, <strong>I1</strong> exhibited significant dose-dependent tumor growth suppression in a Lewis lung carcinoma mouse model without causing observable toxicity, highlighting its potential as a promising lead compound for targeted NSCLC therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109512"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027915","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}