Journal of Medicinal Chemistry最新文献_第6页

HER2-Targeting Affibody Equipped with Albumin-Binding Small Molecules for Radiotheranostics 具有白蛋白结合小分子的her2靶向附着物用于放射治疗

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02269

Weichen Wang,Ao Shen,Mingxing Huang,Rang Wang,Wei Chen,Guangming Shen,Yaguang Wang,Junshan Geng,Zhao Chen,Dawen Niu,Rong Tian,Yingwei Wang

{"title":"HER2-Targeting Affibody Equipped with Albumin-Binding Small Molecules for Radiotheranostics","authors":"Weichen Wang,Ao Shen,Mingxing Huang,Rang Wang,Wei Chen,Guangming Shen,Yaguang Wang,Junshan Geng,Zhao Chen,Dawen Niu,Rong Tian,Yingwei Wang","doi":"10.1021/acs.jmedchem.6c02269","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02269","url":null,"abstract":"Abstract HER2-targeting affibody radioprobes are often limited by rapid systemic clearance and excessive renal accumulation. Herein, we develop a modular chemical strategy to optimize the pharmacokinetic properties of affibodies through conjugation of small-molecule albumin-binding motifs (ABMs). Enabled by our selective S-glycosylation approach, ABMs were introduced via a sugar-based linker, allowing systematic modulation of probe behavior. Evaluation of sugar-modified variants revealed that sugar structure plays a critical role in regulating in vivo distribution, with the GalNAc-modified probe [68Ga]Ga-5c exhibiting favorable tumor-to-background contrast in PET/CT imaging. Further incorporation of ABMs afforded GalNAc-IPBA-functionalized affibody [177Lu]Lu-10a, which achieved an 17-fold extension of circulation half-life, reduced renal accumulation, and maintained efficient tumor targeting. Therapeutically, [177Lu]Lu-10a induced 86.25% tumor growth inhibition with minimal systemic toxicity. This study provides a modular strategy for overcoming pharmacokinetic limitations of affibody-based radiotheranostics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"131 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

The Phenotypic Hit-to-Probe Challenge 表现型撞击探测挑战

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02122

Sven Herschel,Thomas Ullrich,Enrico Schmidt,Jean Quancard,Dennis Schade

引用次数: 0

Ligand-Dependent Affinity but State-Dominated Efficacy in Structure-Based GPCR Pharmacology Prediction 基于结构的GPCR药理学预测中配体依赖的亲和性和状态主导的有效性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02866

Jianxiang Huang,Xin Qiao,Chunhao Zhu,Xiaobing Lan,Shaoyong Lu

{"title":"Ligand-Dependent Affinity but State-Dominated Efficacy in Structure-Based GPCR Pharmacology Prediction","authors":"Jianxiang Huang,Xin Qiao,Chunhao Zhu,Xiaobing Lan,Shaoyong Lu","doi":"10.1021/acs.jmedchem.6c02866","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02866","url":null,"abstract":"Abstract High accuracy in structure-based prediction of G protein-coupled receptor (GPCR) efficacy may reflect the receptor state rather than ligand-specific information. We addressed these information sources using state rules, ligand-blind baselines, matched receptor-state contrasts, ligand permutation, and out-of-distribution (OOD) evaluation, with affinity prediction as a positive control. State rules and ligand-blind geometry achieved binary-efficacy-balanced accuracies of 0.844−0.910 and 0.777−0.870, respectively. Of 75 ligand-aware evaluations, 72 failed at least one prespecified ligand-sensitivity condition, and three lacked required evidence; none met all required criteria. Affinity pretraining gave no detectable efficacy benefit over matched random initialization. In contrast, ligand chemistry supported affinity prediction across 14,740 measured pairs, and all 12 primary affinity permutation comparisons deteriorated, although this advantage did not persist under scaffold, family, or combined OOD splits. Accuracy on endpoint structures therefore cannot alone establish ligand-specific efficacy learning; the findings do not set a general limit on such learning.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Lipid Droplet-Targeted Near-Infrared II Type I AIE Photosensitizer Promotes Ferroptosis by Activating Lipophagy 脂滴靶向近红外II型AIE光敏剂通过激活脂噬促进铁下垂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c01831

Dongxiu Li,Yue Jin,Jiabao Zhuang,Jiawen Chen,Yuhe Zhou,Xue Zhao,Na Zhao,Nan Li

{"title":"Lipid Droplet-Targeted Near-Infrared II Type I AIE Photosensitizer Promotes Ferroptosis by Activating Lipophagy","authors":"Dongxiu Li,Yue Jin,Jiabao Zhuang,Jiawen Chen,Yuhe Zhou,Xue Zhao,Na Zhao,Nan Li","doi":"10.1021/acs.jmedchem.6c01831","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01831","url":null,"abstract":"Abstract Lipophagy, a selective autophagic pathway, maintains lipid homeostasis and contributes to ferroptosis by supplying lipid peroxidation substrates. However, organic photosensitizers that activate lipophagy to promote ferroptosis remain scarce. Herein, we developed a NIR-II emissive photosensitizer (MBTTD) targeting lipid droplets (LDs). Compared with its analogue MBTTA, stronger electron-withdrawing groups bathochromically shifted absorption/emission and tuned excited-state decay, enabling efficient type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency. MBTTD nanoparticles (NPs) localized to LDs upon cellular uptake. Upon 808 nm laser irradiation, MBTTD NP-mediated phototherapy disrupted LDs and induced Rab7-regulated lipophagy, releasing polyunsaturated fatty acids that underwent ROS-driven peroxidation, triggering extensive lipid peroxidation and ferroptosis. Concurrently, MBTTD-NP-mediated phototherapy triggered endoplasmic reticulum stress and apoptosis. MBTTD NPs showed favorable biocompatibility and potent therapeutic efficacy in multicellular tumor spheroids. In vivo studies revealed that MBTTD NPs enabled NIR-II imaging-guided phototherapy, suppressing 4T1 tumor growth without significant systemic toxicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 GTA182, a Novel CNS-Active Tricyclic Amide MTA-Cooperative PRMT5 Inhibitor for MTAP -Deleted Cancers 新型cns活性三环酰胺mta协同PRMT5抑制剂GTA182的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02121

Bing Yao,Weifeng Mao,Minghua Wang,Junqing Zhang,Shanshan Xie,Kai Cheng,Xinbo Hu,Wei Liu,Xiangping Zhang,Zhengqing Zhu,James D. Joseph,Mingxi Li,Xiaohui Gu,Fred Aswad

{"title":"Discovery of GTA182, a Novel CNS-Active Tricyclic Amide MTA-Cooperative PRMT5 Inhibitor for\u0000 MTAP\u0000 -Deleted Cancers","authors":"Bing Yao,Weifeng Mao,Minghua Wang,Junqing Zhang,Shanshan Xie,Kai Cheng,Xinbo Hu,Wei Liu,Xiangping Zhang,Zhengqing Zhu,James D. Joseph,Mingxi Li,Xiaohui Gu,Fred Aswad","doi":"10.1021/acs.jmedchem.6c02121","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02121","url":null,"abstract":"Abstract Developing central nervous system (CNS) active, MTA-cooperative PRMT5 inhibitors for MTAP-deleted malignancies represents a formidable challenge. Here, we report the discovery of GTA182 via structure-based drug design. Multi-parameter optimization balanced single-digit nanomolar potency and &gt;100-fold MTAP-deletion selectivity with dose-proportional pharmacokinetics. Optimized physicochemical properties, and minimal efflux delivered unbound brain concentrations within the efficacious range. Oral GTA182 demonstrated robust MTAP deletion-dependent efficacy, achieving net regression at 30 mg/kg (102% TGI) in MTAP-deleted HCT116 xenografts (versus 41% TGI in WT) alongside 59% regression and extended median survival (&gt;91 days) in the orthotopic U87MG-luc glioblastoma model. In a Phase I trial (CTR20243795), GTA182 was well tolerated, shrank intracranial tumors, and achieved an overall objective response rate (ORR) approaching 30%. These properties establish GTA182 as a promising therapeutic candidate for MTAP-deleted systemic and CNS malignancies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"246 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

FDA Approval of Ensitrelvir: an Oral, Nonpeptidic, Noncovalent SARS-CoV-2 Main Protease Inhibitor for Household Postexposure Prophylaxis FDA批准Ensitrelvir：用于家庭暴露后预防的口服、非肽类、非共价SARS-CoV-2主要蛋白酶抑制剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02923

Ronald A. Besandre,Jun Li,Haiying Chen,Jia Zhou

引用次数: 0

Medicinal Chemistry Strategies for Targeting RNA-Binding Proteins: Design, Optimization, and Therapeutic Potential 靶向rna结合蛋白的药物化学策略：设计、优化和治疗潜力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02201

Bangbang Li,Hao Shen,Zeliang Xu,Yixi Wang,Jiayu Ding,Zhongrui Shi,Chengliang Sun,Peng Yang,Xiao Wang

引用次数: 0

Rethinking log P : Lipophilicity =̷ Hydrophobicity 重新思考log P：亲脂性=疏水性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c01917

Michael D. Shultz,Eric J. Martin

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Discovery of Tricyclic Oxazinoquinolinone-Based BCL6 PROTAC Degraders with Potent Activity Against Diffuse Large B-Cell Lymphoma 三环恶嗪喹啉酮类BCL6 PROTAC降解剂的发现，对弥漫性大b细胞淋巴瘤具有有效活性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c02040

Xuetao Chen,Rujun Xu,Xiaoran Wang,Huidan Wu,Nan Wang,Xin Huang,Wenjing Kang,Qidong You,Xiaoke Guo,Zhengyu Jiang

引用次数: 0

Discovery of Anti-apoptotic BAX Inhibitors 抗凋亡BAX抑制剂的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI: 10.1021/acs.jmedchem.6c01594

Marta Diceglie,Jörg Contzen,Andreas Oder,Arundhasa Chandrabalan,Max Ruwolt,Justin Kale,Anton F. Ketzel,Scott Houliston,Edgar Specker,Silke Radetzki,Keven Mallow,Lina Hellwig,Annette Aigner,Martin Neuenschwander,Justin Philip Pogmore,Tao Xin,Rima Al-Awar,David E. Uehling,Han Sun,Fan Liu,Jens Peter von Kries,David W. Andrews,Philipp Mergenthaler,Marc Nazaré

{"title":"Discovery of Anti-apoptotic BAX Inhibitors","authors":"Marta Diceglie,Jörg Contzen,Andreas Oder,Arundhasa Chandrabalan,Max Ruwolt,Justin Kale,Anton F. Ketzel,Scott Houliston,Edgar Specker,Silke Radetzki,Keven Mallow,Lina Hellwig,Annette Aigner,Martin Neuenschwander,Justin Philip Pogmore,Tao Xin,Rima Al-Awar,David E. Uehling,Han Sun,Fan Liu,Jens Peter von Kries,David W. Andrews,Philipp Mergenthaler,Marc Nazaré","doi":"10.1021/acs.jmedchem.6c01594","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01594","url":null,"abstract":"Abstract BAX is a critical regulator of the apoptosis cascade and its abnormal activation contributes to the development of disease including cardiovascular and neurodegenerative disorders. Therefore, BAX represents an attractive target for the pharmacological inhibition of pathological cell death. Based on a virtual screen, we identified and modified several EGFR kinase inhibitors with potential activity against BAX. Systematic modifications of the dacomitinib and gefitinib core structure were performed, allowing us to elucidate how structural modifications influence biological activity and leading to a comprehensive structure-activity relationship (SAR) on BAX inhibition. The developed series has favorable drug-like properties and improved BAX inhibitory activity in vitro, in cells, and in human induced pluripotent stem cell-derived brain organoids, with significantly reduced EGFR kinase activity. This series therefore represents a promising starting point for the development of improved and potentially therapeutic BAX inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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