European Journal of Medicinal Chemistry最新文献_第2页

Discovery of Benzimidazole-Based Mcl-1 Inhibitors via AlphaShape-Enabled Virtual Screening 通过alphashape虚拟筛选发现基于苯并咪唑的Mcl-1抑制剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI: 10.1016/j.ejmech.2025.118229

Yiming Nie, Jintong Du, Xin Yan, Haihan Liu, Jiaqi Liu, Hu Ge, Hao Fang, Xuben Hou

{"title":"Discovery of Benzimidazole-Based Mcl-1 Inhibitors via AlphaShape-Enabled Virtual Screening","authors":"Yiming Nie, Jintong Du, Xin Yan, Haihan Liu, Jiaqi Liu, Hu Ge, Hao Fang, Xuben Hou","doi":"10.1016/j.ejmech.2025.118229","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118229","url":null,"abstract":"As an essential regulator of tumor cell survival mechanisms, myeloid cell leukemia 1 (Mcl-1) represents a promising anti-cancer target. This study describes the identification of novel benzimidazole scaffolds targeting Mcl-1 through AlphaShape, a deep neural network-empowered shape-based screening program. Through structure-based optimization of the initial hit compound, we developed a series of derivatives exhibiting enhanced binding specificity for Mcl-1 over Bcl-2/Bcl-xL. Notably, compounds 26c and 26d demonstrated submicromolar binding affinities (Ki = 0.59 and 0.74 μM, respectively) with concomitant antiproliferative effects in pancreatic cancer cells through apoptosis induction. Furthermore, the binding mode of 26d was elucidated through an integrated approach combining molecular dynamics simulation and HSQC-NMR spectroscopy. Our findings not only validate AlphaShape as an efficient tool for lead discovery but also provide a strategic framework for developing targeted Mcl-1 inhibitors with therapeutic potential in pancreatic cancer treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"47 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis and biological evaluation of 8-phenylquinazolin-2-amine derivatives as FLT3 covalent inhibitors targeting cysteine 828 in the ATP pocket 靶向半胱氨酸828的FLT3共价抑制剂8-苯基喹唑啉-2胺衍生物的设计、合成及生物学评价

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1016/j.ejmech.2025.118212

Wei Wei, Zuli Hu, Jiuyu Gao, Tianqiong Yang, Qi Zhang, Kaiyan Xu, Chongmin Qin, Lin Yue, Ningyu Wang, Yu Cao, Luoting Yu, Zhihao Liu

{"title":"Design, synthesis and biological evaluation of 8-phenylquinazolin-2-amine derivatives as FLT3 covalent inhibitors targeting cysteine 828 in the ATP pocket","authors":"Wei Wei, Zuli Hu, Jiuyu Gao, Tianqiong Yang, Qi Zhang, Kaiyan Xu, Chongmin Qin, Lin Yue, Ningyu Wang, Yu Cao, Luoting Yu, Zhihao Liu","doi":"10.1016/j.ejmech.2025.118212","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118212","url":null,"abstract":"Targeting oncogenic activating mutations of Fms-Like tyrosine kinase 3 (FLT3) has constituted a promising therapy for acute myeloid leukemia (AML). However, rapid development of resistance has significantly compromised clinical efficacy and therapeutic durability of FLT3 inhibitors. Covalent inhibitors have shown impressive potential in overcoming drug resistance. Herein, we designed and synthesized a series of 8-phenylquinazolin-2-amine derivatives as FLT3 covalent inhibitors targeting cysteine 828. Among them, 4k demonstrated potent and selective inhibitory activities against FLT3-ITD positive AML cells and BaF3 cells harboring drug-resistant FLT3-ITD secondary mutations, including BaF3-FLT3-ITD-D835V/I. Biochemical and mass spectrometry analyses confirmed that 4k covalently bound to the Cys828 in the ATP pocket of FLT3. 4k also inhibited the phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis. Furthermore, 4k, with an oral bioavailability of 12.48%, effectively suppressed tumor growth in a MV4-11 xenograft model without obvious toxicity. Taken together, 4k represents a novel covalent inhibitor targeting Cys828 of FLT3 kinase for targeted therapy of AML.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Y502-2304, a potent c-Myc G-quadruplex stabilizer for the treatment of multiple myeloma Y502-2304的发现，一种有效的c-Myc g -四重稳定剂，用于治疗多发性骨髓瘤

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1016/j.ejmech.2025.118209

Jian Gao , Xinxin Qu , Mengting Li , Pingting Jia , Guanghui Cheng , Jiacheng Yin

{"title":"Discovery of Y502-2304, a potent c-Myc G-quadruplex stabilizer for the treatment of multiple myeloma","authors":"Jian Gao , Xinxin Qu , Mengting Li , Pingting Jia , Guanghui Cheng , Jiacheng Yin","doi":"10.1016/j.ejmech.2025.118209","DOIUrl":"10.1016/j.ejmech.2025.118209","url":null,"abstract":"<div><div>c-Myc is a proto-oncogene that is frequently overexpressed in various cancers, including multiple myeloma (MM), and is associated with poor clinical outcomes. Due to the lack of well-defined small-molecule binding pockets, directly targeting c-Myc remains a formidable challenge. The G-quadruplex (G4) formed in the NHE III1 region of the c-Myc promoter provides an alternative strategy to suppress c-Myc transcription. Given the structural features of thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine that are consistent with G4 stabilizers, we sought to identify novel compounds based on this scaffold. A structural similarity-based virtual screen of the ChemDiv small-molecule library identified 23 of its derivatives, which were prioritized for further investigation. Among these, compound Y502–2304 demonstrated selective stabilization of the c-Myc G4 structure and potent antiproliferative activity in MM cells. Moreover, Y502–2304 dose-dependently downregulated c-Myc mRNA and protein expression while exerting minimal effects on other G4-containing oncogenes. Mechanistically, Y502–2304 induced apoptosis in MM cells, characterized by elevated γH2AX levels, increased reactive oxygen species (ROS) generation, and mitochondrial dysfunction. It also activated the p53 pathway and upregulated the downstream pro-apoptotic proteins Noxa and PUMA. Y502–2304 significantly inhibited tumor growth in a xenograft MM model without inducing notable toxicity in vivo. These findings underscore Y502–2304 as a selective c-Myc G4 stabilizer with strong therapeutic potential for MM.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118209"},"PeriodicalIF":5.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antiviral strategies based on targeted protein degradation: an overview of the literature and future outlook 基于靶向蛋白降解的抗病毒策略：文献综述和未来展望

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1016/j.ejmech.2025.118208

Fan Zhou, Dazhou Shi, Baohu Li, Mei Wang, Shujing Xu, Jinfei Yang, Xu Deng, Peng Zhan

引用次数: 0

Breaking Barriers: Medicinal Chemistry Strategies and Advanced In-Silico Approaches for Overcoming the BBB and Enhancing CNS Penetration 突破障碍：克服血脑屏障和增强中枢神经系统渗透的药物化学策略和先进的硅方法

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1016/j.ejmech.2025.118219

Eneye D. Ajayi, Mahmoud Elazazy, Khaled Abouzid, Hamed I. Ali

{"title":"Breaking Barriers: Medicinal Chemistry Strategies and Advanced In-Silico Approaches for Overcoming the BBB and Enhancing CNS Penetration","authors":"Eneye D. Ajayi, Mahmoud Elazazy, Khaled Abouzid, Hamed I. Ali","doi":"10.1016/j.ejmech.2025.118219","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118219","url":null,"abstract":"Delivering small molecules to the brain and central nervous system (CNS) is greatly hindered by the restrictive blood-brain barrier (BBB), which selectively permits essential molecules while excluding toxic molecules. This selective permeability feature of the membrane also poses a challenge in delivering small molecules to the brain intended for therapeutic benefits. Pharmaceutical approaches such as designing a prodrug, conjugating with liposomes/immunoliposomes, and formulating as nanoparticles have been employed to increase BBB penetration. Despite these efforts, the challenge of suboptimal concentration reaching the brain persists. Modifying small molecules in the early stages of drug discovery is a promising strategy for designing drugs that can penetrate the BBB. To achieve this, it is essential to fine-tune physicochemical parameters to enhance permeability while carefully avoiding toxicity. In this review, we elucidate the most recent strategies for optimizing small molecules by adjusting molecular weight, lipophilicity, pKa, number of hydrogen bond donors, number of rotatable bonds, topological polar surface area, and the ratio of drug concentration in the brain to that in the blood (LogBB). This review will enable researchers to rapidly adopt a framework to overcome BBB challenges in CNS drug discovery by integrating empirical and computational strategies. The insights presented here aim to empower researchers to develop effective BBB-penetrable small molecules, advancing CNS therapeutics and improving the treatment of neurological disorders and brain metastasis.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"78 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disarming superbugs: New frontiers in inhibiting NDM-1 and other clinically relevant metallo-β-lactamases 解除超级细菌：抑制NDM-1和其他临床相关金属β-内酰胺酶的新领域

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-29 DOI: 10.1016/j.ejmech.2025.118220

Pulkit Dhiman , Amit Patwa , Arya B. Narayanan , Aayushi Saini , Ankita Pundir , Manoj D. Dhole , Vinod D. Chaudhari

{"title":"Disarming superbugs: New frontiers in inhibiting NDM-1 and other clinically relevant metallo-β-lactamases","authors":"Pulkit Dhiman , Amit Patwa , Arya B. Narayanan , Aayushi Saini , Ankita Pundir , Manoj D. Dhole , Vinod D. Chaudhari","doi":"10.1016/j.ejmech.2025.118220","DOIUrl":"10.1016/j.ejmech.2025.118220","url":null,"abstract":"<div><div>The emergence and global spread of Metallo-β-lactamases (MBLs), particularly New Delhi Metallo-β-lactamase (NDM), Verona Integron-encoded Metallo-β-lactamase (VIM), and Imipenemase (IMP), pose a significant threat to the efficacy of β-lactam antibiotics, including carbapenems, often regarded as the last line of defence against multidrug-resistant bacterial infections. This review comprehensively analyzes recent advances in the development of MBL inhibitors (MBLIs), targeting NDM, VIM, and IMP enzymes with a special focus on NDM-1. The inhibitors are categorized based on key functional groups responsible for their activity, offering insight into the structure activity relationships (SAR) that govern their potency and selectivity. We highlight representative compounds with potent inhibition data (IC50/Ki values), supported by molecular docking studies and where available co-crystal structures with target MBLs to elucidate their binding interactions. Synthetic approaches for these inhibitors are also discussed. This review aims to provide a detailed, functionally organized framework for ongoing efforts in designing potent, broad-spectrum MBL inhibitors capable of restoring the utility of β-lactam antibiotics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118220"},"PeriodicalIF":5.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lipophilic Integrated Bioorthogonal Self-Catalyzed Nitric Oxide Donor–Platinum(IV) Prodrugs for Enhanced Antitumor Efficacy Against Esophageal Cancer 亲脂性整合生物正交自催化一氧化氮供体-铂（IV）前药增强食管癌抗肿瘤疗效

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-28 DOI: 10.1016/j.ejmech.2025.118221

Ziyu Qian, Xun Yuan, Qing Zhao, Chi Zhang, Jia Shao, Lin Wang, Haoyang Tang, Zirui Su, Mengshuang Huang, Jiayi Xue, Chen Zhang, Huiqin Chen, Ummatjon Gayrat Ugli Mustafaev, Ziqi Pan, Hui Ye, Yihua Zhang, Zhangjian Huang, Shan Yang, Jianbing Wu

{"title":"Lipophilic Integrated Bioorthogonal Self-Catalyzed Nitric Oxide Donor–Platinum(IV) Prodrugs for Enhanced Antitumor Efficacy Against Esophageal Cancer","authors":"Ziyu Qian, Xun Yuan, Qing Zhao, Chi Zhang, Jia Shao, Lin Wang, Haoyang Tang, Zirui Su, Mengshuang Huang, Jiayi Xue, Chen Zhang, Huiqin Chen, Ummatjon Gayrat Ugli Mustafaev, Ziqi Pan, Hui Ye, Yihua Zhang, Zhangjian Huang, Shan Yang, Jianbing Wu","doi":"10.1016/j.ejmech.2025.118221","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118221","url":null,"abstract":"Esophageal cancer (EC) represents a globally prevalent malignancy with limited validated therapeutic targets, for which the cisplatin (CDDP)/5-fluorouracil (5-FU) combination remains the standard chemotherapy backbone. Nitric oxide (NO) and platinum(IV) complexes have attracted significant research interest in antitumor therapy. Previously designed integrated prodrugs suffered from poor cellular uptake. Herein, we reported the design, synthesis, and biological evaluation of a series of novel lipophilic integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs, in which cytoplasmic reductants catalyze the release of Pt(Ⅱ) and NO to produce synergistic antitumor effects in cancer cells. In vitro biological studies revealed that 10k exhibited 1.3- to 4.4-fold lower IC50 values than CDDP against esophageal cancer cell lines, correlating with significantly enhanced lipophilicity. The lipophilic modification at the axial position of complex 10k significantly enhanced cellular Pt accumulation and DNA platination in KYSE-520 cells by 10.4- and 4.7-fold, respectively, compared to CDDP. The preferred complex 10k demonstrated favorable stability and pharmacokinetic properties. Compared with CDDP, 10k exhibited potent in vivo anti-esophageal cancer effects (71.1% tumor growth inhibition (TGI) against the KYSE-520 xenograft model) as well as inhibited lung metastasis, without significant systemic toxicity. Overall, the integrated prodrug 10k represents a promising candidate for EC treatment and deserves further in-depth studies.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"68 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rational design of next-generation FLT3 inhibitors in acute myeloid leukemia: From laboratory to clinics 新一代FLT3抑制剂在急性髓系白血病中的合理设计：从实验室到临床

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-28 DOI: 10.1016/j.ejmech.2025.118214

Shan Gao , Xueting Wang , Xiang Zhao , Zhennan Xiao

{"title":"Rational design of next-generation FLT3 inhibitors in acute myeloid leukemia: From laboratory to clinics","authors":"Shan Gao , Xueting Wang , Xiang Zhao , Zhennan Xiao","doi":"10.1016/j.ejmech.2025.118214","DOIUrl":"10.1016/j.ejmech.2025.118214","url":null,"abstract":"<div><div>Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are among the most common genetic alterations in acute myeloid leukemia (AML), affecting approximately 30 % of patients and leading to a poor prognosis. The development of FLT3-targeted inhibitors has achieved significant progress. First-generation multi-kinase inhibitors like midostaurin and second-generation agents such as gilteritinib and quizartinib have shown success. However, drug resistance, often due to D835Y and F691L gatekeeper mutations, remains a major challenge. In response, a new generation of FLT3 inhibitors (FLT3i) have been designed to simultaneously target both FLT3 internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations. This review examines the mechanisms of FLT3 in the regulation of AML and examines preclinical research on novel FLT3i over the past five years. It discusses how these agents, including small-molecule like STI-8591, compounds 36 and 80 and novel therapeutic strategies such as CLN-049, and SENTI-202, are designed to combat resistance. The goal is to provide a medicinal chemistry perspective to provide insights for the design of novel small-molecule FLT3i.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118214"},"PeriodicalIF":5.9,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel potent indazole-based FXR agonists via scaffold hopping for MASH treatment 通过支架跳跃疗法发现新型强效茚唑类FXR激动剂

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-27 DOI: 10.1016/j.ejmech.2025.118203

Da-Yu Shi , Xin-Wei Shi , Hang Shi , Jing Yu , Qing-Hua Li , Ping Tian , Cheng Huang , Dingding Gao

{"title":"Discovery of novel potent indazole-based FXR agonists via scaffold hopping for MASH treatment","authors":"Da-Yu Shi , Xin-Wei Shi , Hang Shi , Jing Yu , Qing-Hua Li , Ping Tian , Cheng Huang , Dingding Gao","doi":"10.1016/j.ejmech.2025.118203","DOIUrl":"10.1016/j.ejmech.2025.118203","url":null,"abstract":"<div><div>The farnesoid X receptor (FXR) plays a crucial role in regulating bile acid homeostasis, inflammation, fibrosis, as well as glucose and lipid metabolism, positioning it as a promising target for the treatment of Metabolic Associated Steatohepatitis (MASH). LMB763 (Nidufexor), a clinical-stage FXR agonist developed by Novartis, has demonstrated efficacy in alleviating hepatic steatosis, inflammation, and fibrosis in preclinical MASH models. Using LMB763 as a lead compound, a series of novel compounds were designed and synthesized via a scaffold hopping strategy. The lead compound E2 exhibited potent FXR agonist activity with an EC50 value of 0.097 ± 0.009 μM and favorable hepatic microsomal metabolic stability. Additionally, compound E2 displayed good selectivity against related nuclear receptors, including LXRα/β, PPARα/γ/δ, PXR, and TGR5. In vivo evaluation confirmed that compound E2 improved hepatic steatosis in high-fat diet (HFD)-induced MASH mouse model. These findings highlight E2 as a promising candidate for further development and provide valuable insights into the design of selective FXR agonists for MASH treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118203"},"PeriodicalIF":5.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In silico discovery and mechanistic profiling of STING agonists engaging the transmembrane domain 参与跨膜结构域的STING激动剂的硅发现和机制分析

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-27 DOI: 10.1016/j.ejmech.2025.118201

Ahmad Junaid , Uddav Pandey , Janine Ward , Nilesh Meghani , Shannon Miller , Austin Negron , Kendal Ryter , David Burkhart , Nobuyu Mizuno , Victor R. DeFilippis , Omer Rasheed

{"title":"In silico discovery and mechanistic profiling of STING agonists engaging the transmembrane domain","authors":"Ahmad Junaid , Uddav Pandey , Janine Ward , Nilesh Meghani , Shannon Miller , Austin Negron , Kendal Ryter , David Burkhart , Nobuyu Mizuno , Victor R. DeFilippis , Omer Rasheed","doi":"10.1016/j.ejmech.2025.118201","DOIUrl":"10.1016/j.ejmech.2025.118201","url":null,"abstract":"<div><div>Stimulator of interferon genes (STING) is an ER resident cytosolic pattern recognition receptor involved in innate immune signaling and is a promising therapeutic target in immuno-oncology and vaccine adjuvant design. While canonical STING agonists typically activate the receptor via direct engagement with the cytosolic cyclic dinucleotide (CDN)-binding domain (CBD), recent high-resolution structural studies have uncovered a distinct allosteric binding site within the transmembrane domain (TMD). Here, we report the identification and characterization of a novel STING agonist, compound 7k, which uniquely engages the TMD rather than the cytosolic domain. Through comparative molecular docking and binding site validation, the TMD of STING was computationally identified as the preferential site of engagement, diverging from the classical CBD. This mode of activation is functionally significant, as it leads to a demonstrably distinct set of downstream molecular phenotypes. Furthermore, our study led to the discovery of structurally related series of potent, small-molecule human STING activators with potential utility as immunomodulatory therapeutics. A lead compound, 7k, emerged with potent STING-dependent activity in vitro and displayed adjuvant efficacy in vivo, as shown by enhanced antigen-specific IgG production and Th1/Th2 cytokine responses in a genetically humanized STING mouse model. These findings support the TMD as a druggable allosteric site and highlight 7k as a promising candidate for next-generation STING-targeted immunotherapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118201"},"PeriodicalIF":5.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0