Pub Date : 2026-10-14DOI: 10.1021/acs.jmedchem.6c01831
Dongxiu Li,Yue Jin,Jiabao Zhuang,Jiawen Chen,Yuhe Zhou,Xue Zhao,Na Zhao,Nan Li
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.
{"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}
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 >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 (>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.
{"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 >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 (>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}
Pub Date : 2026-10-14DOI: 10.1021/acs.jmedchem.6c02923
Ronald A. Besandre,Jun Li,Haiying Chen,Jia Zhou
{"title":"FDA Approval of Ensitrelvir: an Oral, Nonpeptidic, Noncovalent SARS-CoV-2 Main Protease Inhibitor for Household Postexposure Prophylaxis","authors":"Ronald A. Besandre,Jun Li,Haiying Chen,Jia Zhou","doi":"10.1021/acs.jmedchem.6c02923","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02923","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210307","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}
Pub Date : 2026-10-14DOI: 10.1021/acs.jmedchem.6c02201
Bangbang Li,Hao Shen,Zeliang Xu,Yixi Wang,Jiayu Ding,Zhongrui Shi,Chengliang Sun,Peng Yang,Xiao Wang
Abstract RNA-binding proteins (RBPs) are essential regulators of post-transcriptional gene expression whose disruption contributes broadly to tumor initiation, progression, and therapeutic resistance. Through their control of RNA splicing, stability, translation, and epitranscriptomic modification, these proteins orchestrate oncogenic networks that sustain hallmark cancer phenotypes. This central role has stimulated intensive efforts to develop small-molecule RBP inhibitors, yielding mechanistically diverse compounds against m6A pathway components and classical oncogenic RBPs with demonstrated efficacy in preclinical models. However, substantial challenges remain, including achieving high target selectivity, optimizing drug-like properties, and addressing adaptive resistance mechanisms. This article examines recent advances in RBP-targeted therapeutics, highlighting design strategies, structural mechanisms, and key obstacles on the path toward clinical application.
{"title":"Medicinal Chemistry Strategies for Targeting RNA-Binding Proteins: Design, Optimization, and Therapeutic Potential","authors":"Bangbang Li,Hao Shen,Zeliang Xu,Yixi Wang,Jiayu Ding,Zhongrui Shi,Chengliang Sun,Peng Yang,Xiao Wang","doi":"10.1021/acs.jmedchem.6c02201","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02201","url":null,"abstract":"Abstract RNA-binding proteins (RBPs) are essential regulators of post-transcriptional gene expression whose disruption contributes broadly to tumor initiation, progression, and therapeutic resistance. Through their control of RNA splicing, stability, translation, and epitranscriptomic modification, these proteins orchestrate oncogenic networks that sustain hallmark cancer phenotypes. This central role has stimulated intensive efforts to develop small-molecule RBP inhibitors, yielding mechanistically diverse compounds against m6A pathway components and classical oncogenic RBPs with demonstrated efficacy in preclinical models. However, substantial challenges remain, including achieving high target selectivity, optimizing drug-like properties, and addressing adaptive resistance mechanisms. This article examines recent advances in RBP-targeted therapeutics, highlighting design strategies, structural mechanisms, and key obstacles on the path toward clinical application.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210295","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}
Pub Date : 2026-10-14DOI: 10.1021/acs.jmedchem.6c01917
Michael D. Shultz,Eric J. Martin
Abstract LogP values have served as cutoffs for hit-, lead-, and drug-likeness as well as thresholds for toxicity and ADME decision-making and are often characterized as lipophilicity. When the properties of octanol and the experimental limitations of logP measurements are considered, it becomes clear that logP > 3 must be due to increased hydrophobicity and not lipophilicity. We propose that the partition coefficient between either octanol or water and “the thermodynamic ideal solution” is a useful reference to separately determine octanol solvation (lipophilicity) and aqueous solvation (hydrophilicity). We further propose that the ideal solubility of solids measures “autophilicity”. Aqueous solvation spans many orders of magnitude, yet octanol solvation is much narrower, and thus lipophilicity is nearly constant. Understanding which molecules are hydrophobic, rather than lipophilic, can be critical in interpreting affinity, PK, ADME, safety, and other behaviors of molecules necessitating these more nuanced definitions.
{"title":"Rethinking log\u0000 P\u0000 : Lipophilicity =̷ Hydrophobicity","authors":"Michael D. Shultz,Eric J. Martin","doi":"10.1021/acs.jmedchem.6c01917","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01917","url":null,"abstract":"Abstract LogP values have served as cutoffs for hit-, lead-, and drug-likeness as well as thresholds for toxicity and ADME decision-making and are often characterized as lipophilicity. When the properties of octanol and the experimental limitations of logP measurements are considered, it becomes clear that logP > 3 must be due to increased hydrophobicity and not lipophilicity. We propose that the partition coefficient between either octanol or water and “the thermodynamic ideal solution” is a useful reference to separately determine octanol solvation (lipophilicity) and aqueous solvation (hydrophilicity). We further propose that the ideal solubility of solids measures “autophilicity”. Aqueous solvation spans many orders of magnitude, yet octanol solvation is much narrower, and thus lipophilicity is nearly constant. Understanding which molecules are hydrophobic, rather than lipophilic, can be critical in interpreting affinity, PK, ADME, safety, and other behaviors of molecules necessitating these more nuanced definitions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"188 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210297","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}
Abstract B-cell lymphoma 6 (BCL6) is a key transcriptional repressor involved in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). In this study, scaffold hopping of BI-3802 led to compound 1, a new tricyclic BCL6-targeting ligand. Further optimization of linker architecture and CRBN-recruiting motifs led to compound 15, a potent BCL6 PROTAC degrader, which induced rapid and efficient BCL6 degradation in OCI-LY1 cells (DC50 = 5.32 nM) and displayed potent antiproliferative activity in BCL6-dependent DLBCL cells (IC50 = 3.2 nM). BCL6 degradation was CRBN- and proteasome-dependent and was accompanied by G1-phase arrest and increased p21 and p27 expression. Oral administration of 15 inhibited tumor growth in an OCI-LY1 xenograft model (TGI = 84% at 20 mg/kg) and reduced tumor BCL6 and Ki67 levels without appreciable body-weight loss or overt major-organ histopathology. Overall, compound 15 represents a promising BCL6 PROTAC degrader for DLBCL.
{"title":"Discovery of Tricyclic Oxazinoquinolinone-Based BCL6 PROTAC Degraders with Potent Activity Against Diffuse Large B-Cell Lymphoma","authors":"Xuetao Chen,Rujun Xu,Xiaoran Wang,Huidan Wu,Nan Wang,Xin Huang,Wenjing Kang,Qidong You,Xiaoke Guo,Zhengyu Jiang","doi":"10.1021/acs.jmedchem.6c02040","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02040","url":null,"abstract":"Abstract B-cell lymphoma 6 (BCL6) is a key transcriptional repressor involved in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). In this study, scaffold hopping of BI-3802 led to compound 1, a new tricyclic BCL6-targeting ligand. Further optimization of linker architecture and CRBN-recruiting motifs led to compound 15, a potent BCL6 PROTAC degrader, which induced rapid and efficient BCL6 degradation in OCI-LY1 cells (DC50 = 5.32 nM) and displayed potent antiproliferative activity in BCL6-dependent DLBCL cells (IC50 = 3.2 nM). BCL6 degradation was CRBN- and proteasome-dependent and was accompanied by G1-phase arrest and increased p21 and p27 expression. Oral administration of 15 inhibited tumor growth in an OCI-LY1 xenograft model (TGI = 84% at 20 mg/kg) and reduced tumor BCL6 and Ki67 levels without appreciable body-weight loss or overt major-organ histopathology. Overall, compound 15 represents a promising BCL6 PROTAC degrader for DLBCL.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210304","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}
Pub Date : 2026-10-14DOI: 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
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.
{"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}
Abstract Fibroblast activating protein (FAP) is specifically overexpressed in malignant tumors. The 2-(2′-hydroxyphenyl)-4(3H)-quinazolinone (HPQ) scaffold exhibits hydrophobicity, aggregation-induced emission (AIE). The responsive probes built on HPQ can undergo in situ activation and self-assembling precipitation, enabling prolonged retention in lesion sites. Herein, a FAP-cleavable Cbz-Gly-Pro-sequence was conjugated to the phenolic hydroxyl of HPQ via a self-immolative linker, with phenol/tyrosine moieties for 131I labeling through aliphatic linkers, affording LWH-1 and LWH-2. LWH-3 further incorporated a tetraphenylethylene moiety, a PEG6-triazole-PEG6 linker, and (D-Tyr)5-NH2. All precursors for radioiodination responded efficiently to FAP, releasing HPQ-OH to generate AIE and illuminating tumors for over 48 h. [131I]LWH-3 showed a 2.76-fold higher molar activity than [131I]LWH-2 and an in vivo half-life of 43.66 min. In PC12-FAP xenografts, [131I]LWH-3 achieved outstanding antitumor efficacy with favorable biosafety. Transcriptomic and metabolomic analyses revealed that internal radiotherapy attenuated tumor metabolic adaptability by modulating fatty acid metabolism-associated networks to impair proliferation.
{"title":"FAP-Triggered In Situ Self-Assembly of HPQ in Tumors Empowers 131I Internal Radiotherapy","authors":"Jiang Wu,Yan Hu,Guoqiang Zhou,Benqin Xu,Chenhao Liao,Yumin Chen,Peixin Lin,Panpan Chen,Tingyou Li,Feng Wang","doi":"10.1021/acs.jmedchem.6c02605","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02605","url":null,"abstract":"Abstract Fibroblast activating protein (FAP) is specifically overexpressed in malignant tumors. The 2-(2′-hydroxyphenyl)-4(3H)-quinazolinone (HPQ) scaffold exhibits hydrophobicity, aggregation-induced emission (AIE). The responsive probes built on HPQ can undergo in situ activation and self-assembling precipitation, enabling prolonged retention in lesion sites. Herein, a FAP-cleavable Cbz-Gly-Pro-sequence was conjugated to the phenolic hydroxyl of HPQ via a self-immolative linker, with phenol/tyrosine moieties for 131I labeling through aliphatic linkers, affording LWH-1 and LWH-2. LWH-3 further incorporated a tetraphenylethylene moiety, a PEG6-triazole-PEG6 linker, and (D-Tyr)5-NH2. All precursors for radioiodination responded efficiently to FAP, releasing HPQ-OH to generate AIE and illuminating tumors for over 48 h. [131I]LWH-3 showed a 2.76-fold higher molar activity than [131I]LWH-2 and an in vivo half-life of 43.66 min. In PC12-FAP xenografts, [131I]LWH-3 achieved outstanding antitumor efficacy with favorable biosafety. Transcriptomic and metabolomic analyses revealed that internal radiotherapy attenuated tumor metabolic adaptability by modulating fatty acid metabolism-associated networks to impair proliferation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210329","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}
Pub Date : 2026-10-12DOI: 10.1021/acs.jmedchem.6c02889
Famin Zhang,Xinwang Li,Bin Zhu,Junjie Zhao,Cencen Lei,Feilong Zhou,Duo Ma,Xinhua Liu
Stimulator of interferon genes (STING) is a promising therapeutic target for severe acute pancreatitis (SAP), but effective small-molecule inhibitors remain limited. Here, structure−activity relationship studies identified compound D4 as a potent STING inhibitor with favorable cellular activity and safety. D4 directly engaged STING, inhibited its oligomerization and downstream TBK1/IRF3 signaling, and restored macrophage phagocytosis, autophagic flux, and mitochondrial function while suppressing NOD-like receptor family pyrin domain containing 3(NLRP3)-associated pyroptosis. D4 showed oral exposure with 24.70% bioavailability and no overt toxicity at 1000 mg/kg. In a caerulein/LPS-induced SAP model, D4 markedly reduced pancreatic injury, acinar cell necrosis, inflammatory infiltration, and serum amylase and lipase levels. STING knockdown produced similar protective effects. These findings identify D4 as a promising STING-targeting lead compound for SAP treatment.
{"title":"Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis","authors":"Famin Zhang,Xinwang Li,Bin Zhu,Junjie Zhao,Cencen Lei,Feilong Zhou,Duo Ma,Xinhua Liu","doi":"10.1021/acs.jmedchem.6c02889","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02889","url":null,"abstract":"Stimulator of interferon genes (STING) is a promising therapeutic target for severe acute pancreatitis (SAP), but effective small-molecule inhibitors remain limited. Here, structure−activity relationship studies identified compound D4 as a potent STING inhibitor with favorable cellular activity and safety. D4 directly engaged STING, inhibited its oligomerization and downstream TBK1/IRF3 signaling, and restored macrophage phagocytosis, autophagic flux, and mitochondrial function while suppressing NOD-like receptor family pyrin domain containing 3(NLRP3)-associated pyroptosis. D4 showed oral exposure with 24.70% bioavailability and no overt toxicity at 1000 mg/kg. In a caerulein/LPS-induced SAP model, D4 markedly reduced pancreatic injury, acinar cell necrosis, inflammatory infiltration, and serum amylase and lipase levels. STING knockdown produced similar protective effects. These findings identify D4 as a promising STING-targeting lead compound for SAP treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152133","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}
Pub Date : 2026-10-12DOI: 10.1021/acs.jmedchem.6c01625
Giulia Bononi,Giulia Sibille,Erika Plicanti,Fabio Testori,Giusy L. Fratello,Arianna Maggiora,Iole Mannella,Stefano Sainas,Marta Giorgis,Donatella Boschi,Riccardo Miggiano,Miriana Di Stefano,Lisa Piazza,Carlotta Granchi,Giulio Poli,Tiziano Tuccinardi,Valeria Di Bussolo,Giulia Freer,Mauro Pistello,Davide M. Ferraris,Giorgio Gribaudo,Marco L. Lolli,Filippo Minutolo
Endoplasmic reticulum (ER) oxidoreductases are promising targets for host-targeted antiviral agents (HTAs) because of their essential role in protein folding, including the maturation of viral proteins. Human protein disulfide isomerase family member A3 (PDIA3) is involved in the folding of N-glycosylated client proteins, including viral envelope proteins, making it an attractive but underexplored antiviral target. Here, we describe the discovery of a novel N-hydroxyindole-2-carboxamide class of PDIA3 inhibitors, exemplified by compound AV22 (1o), which effectively inhibits PDIA3 activity and exerts broad-spectrum antiviral activity against major human respiratory viruses. Mechanistic studies indicated that AV22 (1o) increased the release of non-infectious coronavirus particles and reduced disulfide bond formation in the coronavirus spike protein, indicating that its antiviral effect stems from interference with PDIA3 activity. This new class of HTAs provides promising leads for drug discovery targeting viral envelope protein maturation vulnerabilities and is suitable for developing new BSAs.
{"title":"Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses","authors":"Giulia Bononi,Giulia Sibille,Erika Plicanti,Fabio Testori,Giusy L. Fratello,Arianna Maggiora,Iole Mannella,Stefano Sainas,Marta Giorgis,Donatella Boschi,Riccardo Miggiano,Miriana Di Stefano,Lisa Piazza,Carlotta Granchi,Giulio Poli,Tiziano Tuccinardi,Valeria Di Bussolo,Giulia Freer,Mauro Pistello,Davide M. Ferraris,Giorgio Gribaudo,Marco L. Lolli,Filippo Minutolo","doi":"10.1021/acs.jmedchem.6c01625","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01625","url":null,"abstract":"Endoplasmic reticulum (ER) oxidoreductases are promising targets for host-targeted antiviral agents (HTAs) because of their essential role in protein folding, including the maturation of viral proteins. Human protein disulfide isomerase family member A3 (PDIA3) is involved in the folding of N-glycosylated client proteins, including viral envelope proteins, making it an attractive but underexplored antiviral target. Here, we describe the discovery of a novel N-hydroxyindole-2-carboxamide class of PDIA3 inhibitors, exemplified by compound AV22 (1o), which effectively inhibits PDIA3 activity and exerts broad-spectrum antiviral activity against major human respiratory viruses. Mechanistic studies indicated that AV22 (1o) increased the release of non-infectious coronavirus particles and reduced disulfide bond formation in the coronavirus spike protein, indicating that its antiviral effect stems from interference with PDIA3 activity. This new class of HTAs provides promising leads for drug discovery targeting viral envelope protein maturation vulnerabilities and is suitable for developing new BSAs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152141","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}
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