Bioorganic Chemistry最新文献

{"title":"Design, synthesis, anti-acute ischemic stroke (AIS) effect of receptor-interacting protein kinase 1 (RIPK1) inhibitors containing quinazoline structure","authors":"Ruiqi Su ,&nbsp;Jingning Luo ,&nbsp;Xuan Liu ,&nbsp;Jianwen Chen,&nbsp;Jingdi Zhang,&nbsp;Gongyun He,&nbsp;Xueshi Ye,&nbsp;Yuxing Dai,&nbsp;Jingxia Zhang","doi":"10.1016/j.bioorg.2025.109013","DOIUrl":"10.1016/j.bioorg.2025.109013","url":null,"abstract":"<div><div>Receptor-interacting protein kinase 1 (RIPK1) plays a pivotal role in necroptosis, a regulated form of cell death that contributes to neuronal damage and inflammation. RIPK1 inhibitors have emerged as promising therapeutic agents in the treatment of acute ischemic stroke. In this study, a series of novel RIPK1 inhibitors were designed and synthesized based on a new scaffold containing quinazoline and benzotriazole moieties. Their potent inhibitory activity, selectivity for RIPK1 over RIPK3 and anti-necroptotic activity at the cellular level were then evaluated. Notably, compound <strong>9b</strong> emerged as an optimal candidate, offering substantial neuroprotection by inhibiting the phosphorylation of RIPK1, RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL) within the necroptosis pathway. In vivo evaluations in a rat middle cerebral artery occlusion (MCAO) model highlighted compound <strong>9b</strong>'s neuroprotective effect. Initial assessments of the compound revealed its low toxicity, stable metabolic profile, and favorable permeability across the blood-brain barrier, highlighting its promising potential as a therapeutic agent for AIS.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109013"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155427","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":"Inhibition of human and rat placental 3β-hydroxysteroid dehydrogenases by gallates: Combined experimental, 3D-QSAR, and in silico analysis","authors":"Xiulian Yang ,&nbsp;Yilin Xu ,&nbsp;Shaowei Wang ,&nbsp;Yunbing Tang ,&nbsp;Yingfen Ying ,&nbsp;Yang Zhu ,&nbsp;Ren-shan Ge ,&nbsp;Wei Chen ,&nbsp;Yi Liu","doi":"10.1016/j.bioorg.2025.109019","DOIUrl":"10.1016/j.bioorg.2025.109019","url":null,"abstract":"<div><div>Gallates are extensively utilized as additives in food, pharmaceuticals, and cosmetics. Despite their widespread use, their impact on the endocrine system remains poorly understood. This study investigates the potential interaction of gallates with 3β-hydroxysteroid dehydrogenase (3β-HSD), a critical enzyme in placental progesterone synthesis. The inhibitory effects and structure-activity relationship (SAR) and 3D-QSAR of nine gallates on human (h3β-HSD1) and rat (r3β-HSD4) placental enzymes were evaluated. Results revealed that the inhibitory potency of gallates on h3β-HSD1 was dependent on the carbon-chain length in the alcohol moiety. Propyl, butyl, hexyl, octyl, and dodecyl gallates exhibited mixed inhibition with IC₅₀ values of 75.16, 64.59, 25.44, 19.56, and 5.99 μM, respectively, while gallic acid, methyl, ethyl, and cetyl gallates showed no significant inhibition at 100 μM. Similarly, r3β-HSD4 displayed a comparable inhibition pattern but was more sensitive, with IC₅₀ values of 49.60, 31.86, 25.14, 10.79, and 5.91 μM for the same gallates, respectively. Bivariate correlation analysis demonstrated a negative correlation between IC₅₀ values and hydrophobicity, molecular weight, heavy atom number, carbon number, rotatable bonds, fraction of sp3-hybridized carbon atoms, and volume, while a positive correlation was observed with the lowest binding energy. Molecular docking analysis indicated that these gallates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR modeling highlighted the influence of hydrogen bond acceptors and hydrophobic regions on the inhibitory activity of these compounds. The suppression of progesterone production by these gallates in intact JAr cells is influenced not only by their inhibitory potency on h3β-HSD1 but also by their aqueous solubility. These findings provide valuable insights into the endocrine-disrupting potential of gallates and their interaction with 3β-HSDs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109019"},"PeriodicalIF":4.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154880","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":"Design and synthesis of polyhydroxylated azabicyclo[3.3.1]nonane as selective lysosomal α-glucosidase stabilizers enhancing cellular uptake","authors":"Huang-Yi Li ,&nbsp;Ser John Lynon P. Perez ,&nbsp;Hui-Lan Chang ,&nbsp;Hsuan-Hsuan Lo ,&nbsp;Chia-Ning Yang ,&nbsp;Wei-Chieh Cheng","doi":"10.1016/j.bioorg.2025.108994","DOIUrl":"10.1016/j.bioorg.2025.108994","url":null,"abstract":"<div><div>This study presents an efficient synthetic strategy for developing polyhydroxylated azabicyclo[3.3.1]nonane derivatives as selective lysosomal α-glucosidase (GAA) stabilizers. We synthesized the target bridged bicyclic iminosugars through an intramolecular [3 + 2] cycloaddition of monocyclic allyl aldonitrones, followed by N<img>O bond cleavage. These iminosugars showed potent and selective inhibition of GAA, and their distinct conformations were closely linked to inhibitory potency. Enzyme-based evaluations demonstrated that iminosugar <strong>15</strong>, which adopts a chair-chair conformation, was the most potent inhibitor (Ki = 0.7 μM) and provided superior GAA stabilization, as demonstrated by thermal shift and enzyme inactivation assays. Additionally, cell-based studies confirmed that iminosugars <strong>11</strong> and <strong>15</strong> effectively enhanced GAA uptake, resulting in a 2.2 and 3.7-fold increase, respectively, in Pompe fibroblasts. Our findings reveal that bridged bicyclic iminosugars represent a promising class of enzyme stabilizers for lysosomal storage diseases, particularly Pompe disease, by improving enzyme stability and cellular uptake.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108994"},"PeriodicalIF":4.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118488","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":"Non-steroidal anti-inflammatory drugs conjugated ultra-short Peptidomimetics as potent Antibacterials against methicillin resistant S. aureus with anti-inflammatory activity","authors":"Aman Kumar Mahto ,&nbsp;Saleem Akbar ,&nbsp;Avantika Tyagi ,&nbsp;Noor Fatima ,&nbsp;Mairaj Ahmed Ansari ,&nbsp;Mohammad Shahar Yar ,&nbsp;Rikeshwer Prasad Dewangan","doi":"10.1016/j.bioorg.2025.109018","DOIUrl":"10.1016/j.bioorg.2025.109018","url":null,"abstract":"<div><div>Towards design of novel therapeutics against multidrug-resistant (MDR) pathogens, we reported here a focused series of drug-conjugated ultrashort peptidomimetics. Recognizing the moderate antibacterial activity of non-steroidal anti-inflammatory drugs (NSAIDs), the aim of this study was to enhance their antibacterial potential by conjugating them with an amphiphilic tetrapeptide template (H-Orn-Orn-Trp-Trp-NH₂), while preserving their anti-inflammatory effects. These NSAID-peptide conjugates were synthesized <em>via</em> solid phase peptide synthesis and their antibacterial properties were assessed. Within the library, three peptidomimetics (USP-1, USP-2, USP-3) showed potent antibacterial activity, with minimum inhibitory concentrations (MICs) ranging from 1.9 to 62.5 μg/mL against both Gram-positive and Gram-negative bacteria, including MDR methicillin resistant <em>S. aureus</em>. Interestingly, these potent compounds demonstrated non-hemolytic and non-cytotoxic with up to &gt;100-fold higher concentrations than their antibacterial MICs. The antibacterial mode of action studies revealed that these peptidomimetics primarily depolarized and disrupted the bacterial cell membranes at their MICs. Furthermore, resistance development was not observed in MRSA even after 18 passages with continue exposure of their respective sub-MIC concentrations. Importantly, the conjugated NSAIDs retained their anti-inflammatory activity, by selectively inhibiting COX-2 enzyme. Finally, <em>in vivo</em> efficacy studies in mice revealed that optimized conjugates significantly reduced bacterial load and inflammation at a single intra-peritoneal dose of 10 mg/kg. Overall, these conjugates exhibit dual antibacterial and anti-inflammatory properties, coupled with a low propensity for resistance and favourable safety profile, representing them as promising candidates for the treatment of drug-resistant infections.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109018"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118459","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":"Structure-guided design of a potent focal adhesion kinase (FAK) degrader via ternary complex modeling and molecular dynamics simulation","authors":"Chenxu Liu ,&nbsp;Xiaokang Xu ,&nbsp;Yaning Biao ,&nbsp;Yafen Wang ,&nbsp;Yajing Zhang","doi":"10.1016/j.bioorg.2025.109017","DOIUrl":"10.1016/j.bioorg.2025.109017","url":null,"abstract":"<div><div>Focal adhesion kinase (FAK) functions as a critical regulator of integrin-mediated signaling, orchestrating tumor progression and metastasis via both kinase-dependent enzymatic activity and kinase-independent scaffolding functions. Herein, we report the identification of a potent FAK-targeting PROTAC <strong>9c</strong> via structure-guided ternary complex modeling to optimize linker geometry. In MDA-MB-231 cells, <strong>9c</strong> demonstrated subnanomolar FAK degradation potency (DC₅₀ = 3.6 nM), outperforming its parental inhibitor in suppressing cell proliferation, colony formation, migration and invasion. Moreover, <strong>9c</strong> synergized with cisplatin to enhance chemosensitivity. Mechanistic studies revealed that <strong>9c</strong> induces FAK degradation via a VHL-dependent ubiquitin-proteasome pathway. Notably, molecular dynamics simulations confirmed the formation of a stable FAK-<strong>9c</strong>-VHL ternary complex, rationalizing the linker design strategy. Together, this study establishes a structure-guided PROTAC design paradigm for efficient linker optimization, with <strong>9c</strong> serving as a promising lead compound for targeting FAK-driven malignancies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109017"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155429","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":"Galactomannan tetrasaccharide targets mannose receptor to suppress hepatocellular carcinoma growth through ROS/JNK signaling-induced apoptosis and ROS-mediated autophagy-dependent cell death","authors":"Shuying Li ,&nbsp;Han Gao ,&nbsp;Jielin Zhao ,&nbsp;Guirong Wang ,&nbsp;Guofeng Gu","doi":"10.1016/j.bioorg.2025.109012","DOIUrl":"10.1016/j.bioorg.2025.109012","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Studies have documented the antitumor activities of various polysaccharides derived from <em>Antrodia cinnamomea</em> (AC); however, to date, the antitumor activity of the oligosaccharide fragment related to galactomannan polysaccharide in AC remains unreported. In this study, we disclosed that the backbone tetrasaccharide derivative of AC galactomannan, designated as ACP-3, demonstrates specific binding to mannose receptors (MR) on the surface of Hep G2 cells, facilitating its cellular internalization. This interaction thereby elicited potent antiproliferative effects through dual mechanisms: ROS/JNK signaling-induced apoptosis and ROS-mediated autophagy-induced cell death. In vivo studies further validated the tumor-targeting capability of ACP-3, as monotherapy significantly suppresses the growth of H22 solid tumors. Notably, the co-administration of ACP-3 with cyclophosphamide (CTX) could synergistically enhance antitumor activity and concurrently alleviate CTX-induced adverse effects such as weight loss, hepatorenal toxicity, and immune dysfunction. These findings collectively establish ACP-3 as a promising therapeutic candidate for the treatment of HCC.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109012"},"PeriodicalIF":4.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118461","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":"Small molecule screening of RNA aptamers using native mass spectrometry","authors":"Louise M. Sternicki ,&nbsp;Jack W. Klose ,&nbsp;Sally-Ann Poulsen","doi":"10.1016/j.bioorg.2025.109015","DOIUrl":"10.1016/j.bioorg.2025.109015","url":null,"abstract":"<div><div>The intentional targeting of RNA with small molecules is recognized as a viable pathway to new therapeutics with potential to vastly expand the druggable chemical space. The practical considerations to deliberately target RNA are however still largely under development, including optimal methods to identify small molecules for binding to RNA. Native mass spectrometry (nMS) is established as a valuable biophysical screening method for identifying small molecule hits for protein targets but has been used to a much lesser extent with oligonucleotides. Herein we applied nMS to the analysis of binding of two aminoglycoside RNA aptamers with their cognate ligands, related aminoglycoside ligands and a diverse small molecule library of FDA approved drugs. nMS confirmed cognate ligand binding and allowed semi-quantitation of binding strength and selectivity to be determined across all compounds tested. nMS library screening also identified novel binders. This work demonstrates that nMS can be applied for biophysical screening of RNA aptamers and has potential to be developed as an orthogonal screening technology within broader RNA-targeting drug discovery, however with limitations related to the specific challenges presented by the physicochemical properties of RNA.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109015"},"PeriodicalIF":4.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118462","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":"An easily accessible fluorometric probe for selective cyanide detection via nucleophilic addition: Applications to environmental water samples, smartphone, and bio-imaging of fungi and plants","authors":"Boeun Choi,&nbsp;Sooseong Lee,&nbsp;Hyejin Nam,&nbsp;Jae Jun Lee,&nbsp;Cheal Kim","doi":"10.1016/j.bioorg.2025.109014","DOIUrl":"10.1016/j.bioorg.2025.109014","url":null,"abstract":"<div><div>The monitoring of cyanide (CN⁻) is of great significance due to its extreme toxicity to both humans and the environment. In this study, we report a convenient fluorescent sensor <strong>HNIC</strong> ((<em>E</em>)-7-hydroxy-8-(((2-((7-nitrobenzo[<em>c</em>][1,2,5]oxadiazol-4-yl)amino)phenyl)imino)methyl)-2<em>H</em>-chromen-2-one) for detecting CN⁻. On addition of CN⁻, <strong>HNIC</strong> exhibited a blue fluorescence turn-on response in aqueous media. Moreover, <strong>HNIC</strong> could selectively monitor CN⁻ over other interfering ions, with a detection limit of 4.43 μM. The reaction of CN⁻ with <strong>HNIC</strong> was evaluated using Job plot at a 1:1 ratio. To elucidate the mechanism of the nucleophilic attack of CN⁻ on <strong>HNIC</strong>, ESI-MS analysis, ¹H NMR titration, and DFT studies were employed. <strong>HNIC</strong> showed potential for quantifying CN⁻ in environmental water samples (mineral, tap, river, and drinking water). Furthermore, a smartphone application utilizing <strong>HNIC</strong> successfully monitored CN⁻ concentrations in environmental samples. Importantly, <strong>HNIC</strong> could track CN⁻ through bio-imaging in fungi and plants, including white beech mushrooms, onions, and radish sprouts. Therefore, <strong>HNIC</strong> could be employed as a useful tool for detecting highly toxic CN⁻ by triggering the fluorescent turn-on.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109014"},"PeriodicalIF":4.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118489","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":"Design and synthesis of Prostanoid EP4 receptor antagonists for treatment of inflammatory pain","authors":"Huashen Xu ,&nbsp;Min Han ,&nbsp;Ruiyi Ma ,&nbsp;Junning Zhuang ,&nbsp;Xinyue Dong ,&nbsp;Fuqin Liu ,&nbsp;Zhe Wang ,&nbsp;Ruolin Cao ,&nbsp;Maoying Zhang ,&nbsp;Ge Bai ,&nbsp;Xinran Liu ,&nbsp;Huiwen Jiang ,&nbsp;Yu Li ,&nbsp;Yuan Yang ,&nbsp;Zhongbo Liu ,&nbsp;Lihui Wang ,&nbsp;Guoliang Chen","doi":"10.1016/j.bioorg.2025.109005","DOIUrl":"10.1016/j.bioorg.2025.109005","url":null,"abstract":"<div><div>Prostaglandin E2 (PGE2) is the principal proinflammatory prostanoid and is implicated in the pathogenesis of a number of diseases such as pain, fever, arthritis and cancer. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust anti-inflammation and analgesic effect represents an attractive therapy strategy. A series of urea-containing derivatives of novel benzopyrazole scaffold were designed and synthesized through a scaffold hopping strategy. The most promising compound <strong>27i</strong> exhibited the best inhibitory activity against EP4 (<strong>27i</strong> hEP4 IC₅₀ = 6.40 nM). In a mouse model of arthritis (AIA) induced by Freund's complete adjuvant (CFA), compound <strong>27i</strong> significantly reduced the swelling of paws and joints, inflammatory cell infiltration, cartilage damage, pannus formation and bone erosion in the joints of AIA mice in a dose-dependent manner. In the ear swelling model, the anti-inflammatory effect of compound <strong>27i</strong> was superior to celecoxib and E7046. Besides, <strong>27i</strong> possessed good <em>in vivo</em> tolerability in subacute safety evaluation. Collectively, this study provided valuable lead compounds for the treatment of inflammation and pain, which were worthy of further development</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109005"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096376","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":"Usenamine A, an RGS2 inhibitor, exerts anti-NSCLC activity and enhances cytotoxicity of gemcitabine by inducing ER stress and Notch1-mediated autophagy","authors":"Liyuan Cheng ,&nbsp;Hailong Li ,&nbsp;Chenjun Xie ,&nbsp;Keke Kuang ,&nbsp;Baohong Wan ,&nbsp;Peipei Chen ,&nbsp;Hehuan Sui ,&nbsp;Qi Zhao ,&nbsp;Namki Cho ,&nbsp;Ri Cui","doi":"10.1016/j.bioorg.2025.109010","DOIUrl":"10.1016/j.bioorg.2025.109010","url":null,"abstract":"<div><div>Lung cancer is one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent subtype. Gemcitabine is a primary clinical option for the treatment of NSCLC. Nevertheless, it encounters challenges including drug resistance and severe adverse effects. High expression of regulator of G protein signaling 2 (RGS2) is associated with poor prognosis in NSCLC. Usenamine A (UD32–3), a natural compound derived from lichen usnea longissimi, exerts anti-tumor activities in certain types of cancer cells, however, its underlying molecular mechanisms in NSCLC are largely unknown. In this study, we demonstrated for the first time that UD32–3 exerts anti-NSCLC activity by targeting RGS2, thereby suppressing Notch1 to induce autophagy and promoting reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress. Suppression of RGS2 inhibited cell growth by inducing ROS-mediated ER stress and Notch1-mediated autophagy in NSCLC, whereas its overexpression had the opposite effects. Additionally, combined therapy with UD32–3 and gemcitabine exerted synergistic anti-NSCLC activity. Our findings suggest that RGS2 is a promising therapeutic target for the treatment of NSCLC, and combined therapy with UD32–3 and gemcitabine might be an alternative therapeutic strategy for certain NSCLC patients.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109010"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096956","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}