Pub Date : 2026-02-05DOI: 10.1021/acs.jmedchem.5c03503
Danyang Wang, Gengwu Li, Jianguang Liu, Mengxin Li, Xudan Peng, Jinfeng Deng, Shujie Zhao, Kang Zou, Xiaohan Zhang, Dan Liu, Micky D Tortorella, Linping Wu, Shibing Tang
The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and a promising cancer therapeutic target. Using structure-guided design, we developed novel 4-aminopteridin-7(8H)-one derivatives as ATP-competitive mTOR inhibitors. The lead compound T133 (51) demonstrated exceptional mTOR inhibition (Ki = 0.17 nM) with high selectivity, effectively suppressing phosphorylation of downstream effectors, such as AKT, S6K1, and 4EBP1. In HGC-27 gastric cancer cells, T133 potently inhibited proliferation and migration while inducing apoptosis, cell cycle arrest, and autophagy. This efficacy extended to NCI-H1299 lung cancer and T-47D breast cancer cells. In the HGC-27 xenograft mouse model, oral administration of T133 exhibited dose-dependent efficacy comparable to clinical-stage inhibitor PF-04691502, while exhibiting significantly reduced hepatotoxicity, nephrotoxicity, and pulmonary toxicity. Moreover, assessments of T133 on cytochrome P450, hERG, and AMES indicate a favorable safety profile. These findings suggest T133 is a promising mTOR inhibitor, warranting further investigation for cancer therapy.
{"title":"Discovery and Optimization of 4-Aminopteridin-7(8<i>H</i>)-one Derivatives as Potent and Selective mTOR Inhibitors with Favorable Pharmacodynamic and Safety Characteristics.","authors":"Danyang Wang, Gengwu Li, Jianguang Liu, Mengxin Li, Xudan Peng, Jinfeng Deng, Shujie Zhao, Kang Zou, Xiaohan Zhang, Dan Liu, Micky D Tortorella, Linping Wu, Shibing Tang","doi":"10.1021/acs.jmedchem.5c03503","DOIUrl":"10.1021/acs.jmedchem.5c03503","url":null,"abstract":"<p><p>The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and a promising cancer therapeutic target. Using structure-guided design, we developed novel 4-aminopteridin-7(8<i>H</i>)-one derivatives as ATP-competitive mTOR inhibitors. The lead compound T133 (<b>51</b>) demonstrated exceptional mTOR inhibition (<i>K<sub>i</sub></i> = 0.17 nM) with high selectivity, effectively suppressing phosphorylation of downstream effectors, such as AKT, S6K1, and 4EBP1. In HGC-27 gastric cancer cells, T133 potently inhibited proliferation and migration while inducing apoptosis, cell cycle arrest, and autophagy. This efficacy extended to NCI-H1299 lung cancer and T-47D breast cancer cells. In the HGC-27 xenograft mouse model, oral administration of T133 exhibited dose-dependent efficacy comparable to clinical-stage inhibitor PF-04691502, while exhibiting significantly reduced hepatotoxicity, nephrotoxicity, and pulmonary toxicity. Moreover, assessments of T133 on cytochrome P450, hERG, and AMES indicate a favorable safety profile. These findings suggest T133 is a promising mTOR inhibitor, warranting further investigation for cancer therapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117189","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 : 2026-02-05DOI: 10.1021/acs.jmedchem.5c02788
Ahmed S. Abdelsamie, Jelena Konstantinović, Andreas M. Kany, Christian Schütz, Dominik Kolling, Samira Speicher, Andreas Klein, Roya Shafiei, Mélodie Bouté, Katharina Mundry, Yu Mi Park, Brigitta Loretz, Rolf Müller, Jean-Michel Sallenave, Claus-Michael Lehr, Jesko Koehnke, Katharina Rox, Jörg Haupenthal, Anna K. H. Hirsch
Targeting the extracellular protease elastase (LasB) of the high-priority pathogen Pseudomonas aeruginosa is a promising strategy to develop second-generation, narrow-spectrum antibiotics with a novel mode of action. P. aeruginosa is responsible for a variety of infections, particularly of the lung. Herein, we report the structure-based optimization of a previously reported potent and selective phosphonate-based LasB inhibitor scaffold. Having improved the activity while maintaining high selectivity and favorable ADMET properties, we also demonstrate, for the first time within this scaffold, that intravenous administration leads to favorable lung retention. We could rationally align this with in vitro plasma protein binding. We further observed a link between physicochemical properties like logD7.4 and protein binding, including surfactant proteins that can impair compound activity in the lung. This multiparameter optimization paves the way for the exploration of additional indications requiring systemic treatment, such as hospital-acquired or ventilator-associated pneumonia.
{"title":"Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration","authors":"Ahmed S. Abdelsamie, Jelena Konstantinović, Andreas M. Kany, Christian Schütz, Dominik Kolling, Samira Speicher, Andreas Klein, Roya Shafiei, Mélodie Bouté, Katharina Mundry, Yu Mi Park, Brigitta Loretz, Rolf Müller, Jean-Michel Sallenave, Claus-Michael Lehr, Jesko Koehnke, Katharina Rox, Jörg Haupenthal, Anna K. H. Hirsch","doi":"10.1021/acs.jmedchem.5c02788","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02788","url":null,"abstract":"Targeting the extracellular protease elastase (LasB) of the high-priority pathogen <i><i>Pseudomonas aeruginosa</i></i> is a promising strategy to develop second-generation, narrow-spectrum antibiotics with a novel mode of action. <i><i>P. aeruginosa</i></i> is responsible for a variety of infections, particularly of the lung. Herein, we report the structure-based optimization of a previously reported potent and selective phosphonate-based LasB inhibitor scaffold. Having improved the activity while maintaining high selectivity and favorable ADMET properties, we also demonstrate, for the first time within this scaffold, that intravenous administration leads to favorable lung retention. We could rationally align this with <i>in vitro</i> plasma protein binding. We further observed a link between physicochemical properties like logD<sub>7.4</sub> and protein binding, including surfactant proteins that can impair compound activity in the lung. This multiparameter optimization paves the way for the exploration of additional indications requiring systemic treatment, such as hospital-acquired or ventilator-associated pneumonia.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"40 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122274","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 : 2026-02-05DOI: 10.1021/acs.jmedchem.5c03436
Vojtěch Hamala, Martin Kurfiřt, Lucie Červenková Št́astná, Filip Dvořák, Jana Bernášková, Adéla Sýkorová, Jaroslav Kozák, Martin Zavřel, Tatiana Staroňová, Peter Šebest, Veronika Ostatná, Jakub Červený, Pavla Bojarová, Jitka Holčáková, Tomáš Hrstka, Roman Hrstka, Jindřich Karban
Human galectin-1 (hGal-1) is an abundant β-galactoside-binding animal lectin that plays an essential role in promoting the immunosuppressive tumor microenvironment. Although hGal-1 has been identified as a promising target for pharmacological inhibition, developing potent and selective hGal-1 inhibitors has been complicated by the high degree of sequence similarity of the glycan-binding site across the galectin family. Herein, we present potent nanomolar hGal-1 inhibitors with unprecedented selectivity of 2 to 3 orders of magnitude over human galectin-3 (hGal-3). Their primary structural feature is the modification of a thiodigalactoside scaffold at the 3- and 3′-positions with a half-sandwich ruthenium(II) arene complex containing a bidentate 4-(2-pyridyl)-1H-1,2,3-triazol-1-yl ligand. The most potent inhibitor in the series efficiently blocked the binding of hGal-1 to the surface of MDA-MB-231 tumor cells, reduced their viability, and completely suppressed hGal-1-induced phosphatidylserine exposure in Jurkat cells, a process previously described as preaparesis rather than classical apoptosis.
{"title":"Organoruthenium Glycomimetics Exhibit High Selectivity and Nanomolar Affinity for Human Galectin-1","authors":"Vojtěch Hamala, Martin Kurfiřt, Lucie Červenková Št́astná, Filip Dvořák, Jana Bernášková, Adéla Sýkorová, Jaroslav Kozák, Martin Zavřel, Tatiana Staroňová, Peter Šebest, Veronika Ostatná, Jakub Červený, Pavla Bojarová, Jitka Holčáková, Tomáš Hrstka, Roman Hrstka, Jindřich Karban","doi":"10.1021/acs.jmedchem.5c03436","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03436","url":null,"abstract":"Human galectin-1 (<i>h</i>Gal-1) is an abundant β-galactoside-binding animal lectin that plays an essential role in promoting the immunosuppressive tumor microenvironment. Although <i>h</i>Gal-1 has been identified as a promising target for pharmacological inhibition, developing potent and selective <i>h</i>Gal-1 inhibitors has been complicated by the high degree of sequence similarity of the glycan-binding site across the galectin family. Herein, we present potent nanomolar <i>h</i>Gal-1 inhibitors with unprecedented selectivity of 2 to 3 orders of magnitude over human galectin-3 (<i>h</i>Gal-3). Their primary structural feature is the modification of a thiodigalactoside scaffold at the 3- and 3′-positions with a half-sandwich ruthenium(II) arene complex containing a bidentate 4-(2-pyridyl)-1<i>H</i>-1,2,3-triazol-1-yl ligand. The most potent inhibitor in the series efficiently blocked the binding of <i>h</i>Gal-1 to the surface of MDA-MB-231 tumor cells, reduced their viability, and completely suppressed <i>h</i>Gal-1-induced phosphatidylserine exposure in Jurkat cells, a process previously described as preaparesis rather than classical apoptosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"220 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122294","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 : 2026-02-05DOI: 10.1021/acs.jmedchem.5c02796
Daniel H. Haymer, Renn A. Duncan, Alice L. Rodriguez, Allie Han, Richard J. Lindsay, N. Kithmini Wijesiri, Analisa Thompson Gray, Srinivasan Krishnan, Aidong Qi, Benjamin P. Brown, Olivier Boutaud, Darren W. Engers, Carrie K. Jones, Colleen M. Niswender, Craig W. Lindsley, Aaron M. Bender
Herein, we report the identification of the HIV protease inhibitor amprenavir as a selective cannabinoid receptor 2 (CB2) agonist and describe structure–activity relationship (SAR) studies toward repurposing this peripherally restricted scaffold for high CB2 potency and CNS exposure. This exercise yielded compounds with exceptional CB2 potency (EC50s <10 nM), no appreciable activity at the CB1 receptor, and high predicted permeability/low P-gp efflux activity. Selected compounds were profiled in rat i.v. dosing cassettes; several novel amprenavir analogues displayed good t1/2 (>2 h), moderate plasma clearance, and appreciable brain exposure. Additionally, fully flexible protein–ligand docking studies with molecular dynamics (MD) simulations were used to predict the most likely mode of interaction of highly potent analogue VU6077967 with CB2 and to provide a rationale for the observed selectivity of this series relative to CB1.
{"title":"Drug Repurposing: Conversion of the Peripherally Restricted HIV Protease Inhibitor Amprenavir to Potent, Selective, and CNS-Penetrant Agonists for the Cannabinoid Receptor 2","authors":"Daniel H. Haymer, Renn A. Duncan, Alice L. Rodriguez, Allie Han, Richard J. Lindsay, N. Kithmini Wijesiri, Analisa Thompson Gray, Srinivasan Krishnan, Aidong Qi, Benjamin P. Brown, Olivier Boutaud, Darren W. Engers, Carrie K. Jones, Colleen M. Niswender, Craig W. Lindsley, Aaron M. Bender","doi":"10.1021/acs.jmedchem.5c02796","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02796","url":null,"abstract":"Herein, we report the identification of the HIV protease inhibitor amprenavir as a selective cannabinoid receptor 2 (CB<sub>2</sub>) agonist and describe structure–activity relationship (SAR) studies toward repurposing this peripherally restricted scaffold for high CB<sub>2</sub> potency and CNS exposure. This exercise yielded compounds with exceptional CB<sub>2</sub> potency (EC<sub>50</sub>s <10 nM), no appreciable activity at the CB<sub>1</sub> receptor, and high predicted permeability/low P-gp efflux activity. Selected compounds were profiled in rat i.v. dosing cassettes; several novel amprenavir analogues displayed good <i>t</i><sub>1/2</sub> (>2 h), moderate plasma clearance, and appreciable brain exposure. Additionally, fully flexible protein–ligand docking studies with molecular dynamics (MD) simulations were used to predict the most likely mode of interaction of highly potent analogue VU6077967 with CB<sub>2</sub> and to provide a rationale for the observed selectivity of this series relative to CB<sub>1</sub>.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116009","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}
Phosphodiesterase 4 (PDE4) is a key target for COPD anti-inflammatory drugs. The approved oral PDE4 inhibitor for COPD causes side effects such as nausea and vomiting due to high systemic exposure. Developing highly selective PDE4 inhibitors suitable for inhaled delivery represents an effective alternative strategy. Herein, we report the identification of P29, a PDE4 inhibitor exhibiting picomolar inhibitory potency (IC50 = 0.019 nM) and high selectivity (>10,000) over other PDEs. Subsequent studies demonstrated that P29 effectively suppressed LPS-induced TNF-α release in PBMCs. Notably, the fractions absorbed via pulmonary deposition and orally absorbed fractions were rapidly metabolized, reducing systemic exposure and minimizing adverse reactions. P29 significantly improved pulmonary function, inhibited inflammatory cell activity, reduced release of inflammatory cytokines, and ameliorated lung tissue damage in rat models of COPD induced by cigarette smoke and LPS. Collectively, our data highlight the therapeutic potential of P29 in COPD.
{"title":"Discovery, Synthesis, and Biological Evaluation of Novel Quinoline-Based PDE4 Inhibitors with Potent Anti-Chronic Obstructive Pulmonary Disease Activity","authors":"Gang Xing, Yucong Bi, Zhenli Li, Zhengxing Zhi, Haitao Li, Maosheng Cheng","doi":"10.1021/acs.jmedchem.5c02775","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02775","url":null,"abstract":"Phosphodiesterase 4 (PDE4) is a key target for COPD anti-inflammatory drugs. The approved oral PDE4 inhibitor for COPD causes side effects such as nausea and vomiting due to high systemic exposure. Developing highly selective PDE4 inhibitors suitable for inhaled delivery represents an effective alternative strategy. Herein, we report the identification of P29, a PDE4 inhibitor exhibiting picomolar inhibitory potency (IC<sub>50</sub> = 0.019 nM) and high selectivity (>10,000) over other PDEs. Subsequent studies demonstrated that P29 effectively suppressed LPS-induced TNF-α release in PBMCs. Notably, the fractions absorbed via pulmonary deposition and orally absorbed fractions were rapidly metabolized, reducing systemic exposure and minimizing adverse reactions. P29 significantly improved pulmonary function, inhibited inflammatory cell activity, reduced release of inflammatory cytokines, and ameliorated lung tissue damage in rat models of COPD induced by cigarette smoke and LPS. Collectively, our data highlight the therapeutic potential of P29 in COPD.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122292","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 : 2026-02-04DOI: 10.1021/acs.jmedchem.5c02948
Ye-Si Huang,Jing Liu,Mei-Yan Huang,Yu-Jing Wang,Wei-Min Chen,Jing Lin
Biofilm formation is a crucial determinant of both pathogenicity and enhanced antibiotic resistance in Pseudomonas aeruginosa. Sustainable iron utilization in the bacterial growth environments and intracellular c-di-GMP signaling molecules are key factors promoting bacterial biofilm development. Capitalizing on our previous findings that c-di-GMP G-quadruplex inducers exhibit potent antibiofilm activity and that 3-hydroxypyridin-4(1H)-ones act as effective iron chelators, we designed and synthesized dual-functional hybrid molecules incorporating both pharmacophores. The lead compound 11f, which features a benzothiazole-pyridinone scaffold, demonstrated potent biofilm inhibition against both wild-type P. aeruginosa PAO1 and the hyper-biofilm-forming PAO1-ΔwspF mutant. Mechanistic investigations revealed that 11f operates through dual pathways: facilitating c-di-GMP G-quadruplex formation and disrupting iron acquisition systems. Notably, in Galleria mellonella infection models, 11f exhibited significant synergistic effects with ciprofloxacin and tobramycin while maintaining an excellent safety profile, highlighting its potential as an antibacterial adjuvant.
生物膜的形成是铜绿假单胞菌致病性和增强抗生素耐药性的关键决定因素。细菌生长环境中铁的可持续利用和细胞内c-di-GMP信号分子是促进细菌生物膜发育的关键因素。利用我们之前的发现，c-二- gmp g -四重诱导剂具有有效的抗生物膜活性，3-羟基吡啶-4(1H)- 1作为有效的铁螯合剂，我们设计并合成了包含两种药效团的双功能杂交分子。先导化合物11f具有苯并噻唑-吡啶酮支架，对野生型铜绿假单胞菌PAO1和超生物膜形成PAO1-ΔwspF突变体均有有效的生物膜抑制作用。机制研究表明11f通过双重途径起作用：促进c-二- gmp g -四联体形成和破坏铁获取系统。值得注意的是，在mellonella Galleria感染模型中，11f与环丙沙星和妥布霉素表现出显著的协同效应，同时保持良好的安全性，突出了其作为抗菌佐剂的潜力。
{"title":"Cyclic Diguanylate G-Quadruplex Inducer–Siderophore Hybrids as Bifunctional Antibiofilm Agents against Pseudomonas aeruginosa","authors":"Ye-Si Huang,Jing Liu,Mei-Yan Huang,Yu-Jing Wang,Wei-Min Chen,Jing Lin","doi":"10.1021/acs.jmedchem.5c02948","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02948","url":null,"abstract":"Biofilm formation is a crucial determinant of both pathogenicity and enhanced antibiotic resistance in Pseudomonas aeruginosa. Sustainable iron utilization in the bacterial growth environments and intracellular c-di-GMP signaling molecules are key factors promoting bacterial biofilm development. Capitalizing on our previous findings that c-di-GMP G-quadruplex inducers exhibit potent antibiofilm activity and that 3-hydroxypyridin-4(1H)-ones act as effective iron chelators, we designed and synthesized dual-functional hybrid molecules incorporating both pharmacophores. The lead compound 11f, which features a benzothiazole-pyridinone scaffold, demonstrated potent biofilm inhibition against both wild-type P. aeruginosa PAO1 and the hyper-biofilm-forming PAO1-ΔwspF mutant. Mechanistic investigations revealed that 11f operates through dual pathways: facilitating c-di-GMP G-quadruplex formation and disrupting iron acquisition systems. Notably, in Galleria mellonella infection models, 11f exhibited significant synergistic effects with ciprofloxacin and tobramycin while maintaining an excellent safety profile, highlighting its potential as an antibacterial adjuvant.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111158","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}
Interleukin-1 receptor-associated kinase 1 (IRAK1) is a critical mediator of Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) signaling, and its aberrant activation is implicated in the pathogenesis of various cancers, including hepatocellular carcinoma (HCC). However, the development of clinical IRAK1 inhibitors has been hampered by a lack of sufficient selectivity over other kinases. Herein, we report the discovery of a novel IRAK1 inhibitor, A34, identified through structure-based virtual screening and structural optimization. A34 potently inhibited IRAK1 with an IC50 value of 10.6 nM and demonstrated exceptional selectivity over 215 other kinases, notably including IRAK4. Furthermore, A34 demonstrated significant anti-HCC activity both in vivo and in vitro, making it a valuable chemical probe for IRAK1 and a potential lead candidate for the treatment of HCC.
{"title":"Discovery of Novel, Potent, and Selective IRAK1 Inhibitors as Potential Therapeutics for Hepatocellular Carcinoma","authors":"Wenjian Min,Junfeng He,Qiman Zhang,Chunling Chen,Yanyin Wang,Yuanyuan Chen,Yunchu Zhao,Yi Hou,Chengliang Sun,Xiao Wang,Kai Yuan,Yasheng Zhu,Peng Yang","doi":"10.1021/acs.jmedchem.5c02988","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02988","url":null,"abstract":"Interleukin-1 receptor-associated kinase 1 (IRAK1) is a critical mediator of Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) signaling, and its aberrant activation is implicated in the pathogenesis of various cancers, including hepatocellular carcinoma (HCC). However, the development of clinical IRAK1 inhibitors has been hampered by a lack of sufficient selectivity over other kinases. Herein, we report the discovery of a novel IRAK1 inhibitor, A34, identified through structure-based virtual screening and structural optimization. A34 potently inhibited IRAK1 with an IC50 value of 10.6 nM and demonstrated exceptional selectivity over 215 other kinases, notably including IRAK4. Furthermore, A34 demonstrated significant anti-HCC activity both in vivo and in vitro, making it a valuable chemical probe for IRAK1 and a potential lead candidate for the treatment of HCC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"117 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111159","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}
Cancer drug response prediction is crucial for precision medicine, as it can improve treatment outcomes and reduce medical costs. However, existing models often ignore the geometric features of drug molecules and their interactions with cancer cells. To address this, this study proposes a multiomics fusion model named MTEGDRP. The model uses a transformer to extract high-level features from drug and cell data, as well as their interactions, while an equivariant graph neural network captures the spatial structure of drugs. In regression tasks, MTEGDRP performs better than current state-of-the-art methods. Ablation studies show that multiomics integration and molecular spatial information are effective. Visualization of the feature weights provides interpretability for the model. With its excellent prediction performance, MTEGDRP shows great potential as a useful tool for guiding anticancer drug design in precision medicine.
{"title":"MTEGDRP: Interpretable Molecular Self-Attention Transformer and Equivariant Graph Neural Network Based on Multi-Omics Fusion for Drug Response Prediction in Cancer Cell Lines","authors":"Zhihan Liu,Kairui Lyu,Ya Li,Xinghui Sun,Xin Gao,Bin Yu","doi":"10.1021/acs.jmedchem.5c03438","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03438","url":null,"abstract":"Cancer drug response prediction is crucial for precision medicine, as it can improve treatment outcomes and reduce medical costs. However, existing models often ignore the geometric features of drug molecules and their interactions with cancer cells. To address this, this study proposes a multiomics fusion model named MTEGDRP. The model uses a transformer to extract high-level features from drug and cell data, as well as their interactions, while an equivariant graph neural network captures the spatial structure of drugs. In regression tasks, MTEGDRP performs better than current state-of-the-art methods. Ablation studies show that multiomics integration and molecular spatial information are effective. Visualization of the feature weights provides interpretability for the model. With its excellent prediction performance, MTEGDRP shows great potential as a useful tool for guiding anticancer drug design in precision medicine.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"57 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111160","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 : 2026-02-04DOI: 10.1021/acs.jmedchem.5c02614
Hikaru Ishikura,Callum S. Begg,Juan J. Rojas,Luka Blagojevic,Gavin J. Smith,Joyce Luk,Rosemary A. Croft,Charles Romain,Chulho Choi,James A. Bull
Oxetanes display properties comparable to ketone carbonyl groups and are increasingly explored as bioisosteres. However, does the comparison hold for the most common carbonyl derivatives: do amino-oxetanes resemble amides? Here, we present a matched molecular pair study of 12 3-aryl-3-amino-oxetane and benzamide matched molecular pairs to assess their viability as isosteres. Across the surveyed physicochemical properties (pH stability, solubility, lipophilicity, clearance, permeability), amino-oxetanes exhibited broadly comparable profiles to their amide counterparts. Amino-oxetanes maintain both the H-bond acceptor and H-bond donor capabilities of analogous amides. These findings support the potential of amino-oxetanes as amide replacements. However, crystal structure analysis highlights the conformational differences and alternative exit vectors available through introduction of the oxetane ring. The preferred gauche conformation makes the torsion angle and exit vectors of amino-oxetanes more similar to sulfonamides, and therefore better like-for-like topological replacements. Overall, amino-oxetanes present an attractive design option to modulate physicochemical properties and chemical topology.
{"title":"Do Amino-Oxetanes Resemble Amides? A Matched Molecular Pairs Property and Structural Comparison","authors":"Hikaru Ishikura,Callum S. Begg,Juan J. Rojas,Luka Blagojevic,Gavin J. Smith,Joyce Luk,Rosemary A. Croft,Charles Romain,Chulho Choi,James A. Bull","doi":"10.1021/acs.jmedchem.5c02614","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02614","url":null,"abstract":"Oxetanes display properties comparable to ketone carbonyl groups and are increasingly explored as bioisosteres. However, does the comparison hold for the most common carbonyl derivatives: do amino-oxetanes resemble amides? Here, we present a matched molecular pair study of 12 3-aryl-3-amino-oxetane and benzamide matched molecular pairs to assess their viability as isosteres. Across the surveyed physicochemical properties (pH stability, solubility, lipophilicity, clearance, permeability), amino-oxetanes exhibited broadly comparable profiles to their amide counterparts. Amino-oxetanes maintain both the H-bond acceptor and H-bond donor capabilities of analogous amides. These findings support the potential of amino-oxetanes as amide replacements. However, crystal structure analysis highlights the conformational differences and alternative exit vectors available through introduction of the oxetane ring. The preferred gauche conformation makes the torsion angle and exit vectors of amino-oxetanes more similar to sulfonamides, and therefore better like-for-like topological replacements. Overall, amino-oxetanes present an attractive design option to modulate physicochemical properties and chemical topology.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111156","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 : 2026-02-04DOI: 10.1021/acs.jmedchem.5c01679
Anas Ansari,Koon Mook Kang,Huiying Li,Christine D. Hardy,Athri D. Rathnayake,Amardeep Awasthi,Thomas L. Poulos,Richard B. Silverman
Neuronal nitric oxide synthase (nNOS) is a key enzyme in neurodegenerative diseases and melanoma, making it an important therapeutic target. We previously reported 2-aminoquinoline-based nNOS inhibitors with promising activity but limited by suboptimal potency, isoform selectivity, and off-target effects. To address these issues, we designed and synthesized a new series of 7-aryl-6-fluoro-4-methyl-2-aminoquinoline derivatives. Compound 16 showed excellent potency against human nNOS (Ki 16 nM), with ∼1800-fold selectivity over human endothelial NOS (eNOS) and ∼2900-fold over human inducible NOS (iNOS). PAMPA-BBB experiments indicated high effective permeability (Pe = 13.04 × 10–6 cm/s), suggesting strong CNS drug potential. In vivo pharmacokinetic studies in mice further demonstrated sustained systemic exposure, low clearance, and robust brain penetration. In contrast, compound 24, the N-Me analogue of 16, was inactive. Molecular dynamics simulations indicated that N-methylation disrupted the favorable solvation of the tail amino group, likely contributing to its loss of activity and nNOS affinity.
{"title":"Enhancement of Potency and Selectivity of 2-Aminoquinoline-Based Human Neuronal Nitric Oxide Synthase Inhibitors","authors":"Anas Ansari,Koon Mook Kang,Huiying Li,Christine D. Hardy,Athri D. Rathnayake,Amardeep Awasthi,Thomas L. Poulos,Richard B. Silverman","doi":"10.1021/acs.jmedchem.5c01679","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01679","url":null,"abstract":"Neuronal nitric oxide synthase (nNOS) is a key enzyme in neurodegenerative diseases and melanoma, making it an important therapeutic target. We previously reported 2-aminoquinoline-based nNOS inhibitors with promising activity but limited by suboptimal potency, isoform selectivity, and off-target effects. To address these issues, we designed and synthesized a new series of 7-aryl-6-fluoro-4-methyl-2-aminoquinoline derivatives. Compound 16 showed excellent potency against human nNOS (Ki 16 nM), with ∼1800-fold selectivity over human endothelial NOS (eNOS) and ∼2900-fold over human inducible NOS (iNOS). PAMPA-BBB experiments indicated high effective permeability (Pe = 13.04 × 10–6 cm/s), suggesting strong CNS drug potential. In vivo pharmacokinetic studies in mice further demonstrated sustained systemic exposure, low clearance, and robust brain penetration. In contrast, compound 24, the N-Me analogue of 16, was inactive. Molecular dynamics simulations indicated that N-methylation disrupted the favorable solvation of the tail amino group, likely contributing to its loss of activity and nNOS affinity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111155","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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