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Discovery and Optimization of 4-Aminopteridin-7(8H)-one Derivatives as Potent and Selective mTOR Inhibitors with Favorable Pharmacodynamic and Safety Characteristics. 4-氨基蝶呤-7(8H)- 1衍生物的发现和优化是有效和选择性的mTOR抑制剂,具有良好的药效学和安全性特性。
IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-05 DOI: 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.

雷帕霉素(mTOR)的机制靶点是细胞生长的中心调节剂,是一种很有前景的癌症治疗靶点。利用结构导向设计,我们开发了新的4-氨基蝶呤-7(8H)- 1衍生物作为atp竞争性mTOR抑制剂。先导化合物T133(51)表现出高选择性的特殊mTOR抑制作用(Ki = 0.17 nM),有效抑制下游效应物,如AKT、S6K1和4EBP1的磷酸化。在HGC-27胃癌细胞中,T133能有效抑制增殖和迁移,同时诱导细胞凋亡、细胞周期阻滞和自噬。这种疗效扩展到NCI-H1299肺癌细胞和T-47D乳腺癌细胞。在HGC-27异种移植小鼠模型中,口服T133表现出与临床期抑制剂PF-04691502相当的剂量依赖性疗效,同时表现出显著降低的肝毒性、肾毒性和肺毒性。此外,对细胞色素P450、hERG和AMES的评估表明T133具有良好的安全性。这些发现表明T133是一种很有前景的mTOR抑制剂,值得进一步研究用于癌症治疗。
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引用次数: 0
Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration 铜绿假单胞菌弹性酶抑制剂的多参数优化
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-05 DOI: 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.
针对高优先级病原菌铜绿假单胞菌的胞外蛋白酶弹性酶(LasB)是开发具有新作用模式的第二代窄谱抗生素的有希望的策略。铜绿假单胞菌可引起多种感染,尤其是肺部感染。在此,我们报告了先前报道的有效和选择性膦酸盐基LasB抑制剂支架的结构优化。在提高活性的同时保持高选择性和良好的ADMET特性,我们还首次在该支架中证明静脉给药可导致良好的肺潴留。我们可以合理地将其与体外血浆蛋白结合结合。我们进一步观察到logD7.4等理化性质与蛋白质结合之间的联系,包括可以损害肺中化合物活性的表面活性剂蛋白质。这种多参数优化为探索需要全身治疗的其他适应症铺平了道路,例如医院获得性或呼吸机相关性肺炎。
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引用次数: 0
Organoruthenium Glycomimetics Exhibit High Selectivity and Nanomolar Affinity for Human Galectin-1 有机钌糖仿制品对人半乳糖凝集素-1具有高选择性和纳米摩尔亲和力
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-05 DOI: 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.
人半乳糖凝集素-1 (hGal-1)是一种丰富的β-半乳糖苷结合动物凝集素,在促进免疫抑制肿瘤微环境中起重要作用。尽管hGal-1已被确定为一个有希望的药理学抑制靶点,但由于整个凝集素家族中聚糖结合位点的高度序列相似性,开发有效的、选择性的hGal-1抑制剂变得复杂。在此,我们提出了有效的纳米摩尔hGal-1抑制剂,其选择性比人半乳糖凝集素-3 (hGal-3)高2到3个数量级。他们的主要结构特征的修改thiodigalactoside支架3 - 3的位置与half-sandwich钌(II)芳烃复杂的包含一个双齿4 - (2-pyridyl)的h - 1, 2, 3-triazol-1-yl配体。该系列中最有效的抑制剂有效阻断hGal-1与MDA-MB-231肿瘤细胞表面的结合,降低其活力,并完全抑制hGal-1诱导的Jurkat细胞中磷脂酰丝氨酸暴露,这一过程先前被描述为预凋亡而不是经典的凋亡。
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引用次数: 0
Drug Repurposing: Conversion of the Peripherally Restricted HIV Protease Inhibitor Amprenavir to Potent, Selective, and CNS-Penetrant Agonists for the Cannabinoid Receptor 2 药物再利用:将外周限制性HIV蛋白酶抑制剂Amprenavir转化为大麻素受体2的强效、选择性和cns渗透激动剂
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-05 DOI: 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.
在此,我们报告了HIV蛋白酶抑制剂amprenavir作为选择性大麻素受体2 (CB2)激动剂的鉴定,并描述了结构-活性关系(SAR)研究,以重新利用这种外周限制性支架来实现高CB2效力和中枢神经系统暴露。该实验产生的化合物具有特殊的CB2效力(ec50 <10 nM),对CB1受体没有明显的活性,预测渗透率高/ P-gp外排活性低。选定的化合物在大鼠静脉给药盒中进行了谱图分析;几种新型安非那韦类似物表现出良好的t1/2 (> 2h),中度血浆清除率和明显的脑暴露。此外,利用分子动力学(MD)模拟的全柔性蛋白配体对接研究,预测了高效类似物VU6077967与CB2最可能的相互作用模式,并为该系列相对于CB1的选择性提供了理论依据。
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引用次数: 0
Discovery, Synthesis, and Biological Evaluation of Novel Quinoline-Based PDE4 Inhibitors with Potent Anti-Chronic Obstructive Pulmonary Disease Activity 具有有效抗慢性阻塞性肺疾病活性的新型喹啉类PDE4抑制剂的发现、合成和生物学评价
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-05 DOI: 10.1021/acs.jmedchem.5c02775
Gang Xing, Yucong Bi, Zhenli Li, Zhengxing Zhi, Haitao Li, Maosheng Cheng
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.
磷酸二酯酶4 (PDE4)是COPD抗炎药物的关键靶点。经批准的用于慢性阻塞性肺病的口服PDE4抑制剂由于高系统性暴露导致恶心和呕吐等副作用。开发适合吸入给药的高选择性PDE4抑制剂是一种有效的替代策略。在此,我们报告了P29的鉴定,P29是一种PDE4抑制剂,具有皮摩尔抑制效力(IC50 = 0.019 nM)和高选择性(>10,000)。随后的研究表明,P29可有效抑制lps诱导的pbmc中TNF-α的释放。值得注意的是,通过肺沉积吸收的部分和口服吸收的部分被迅速代谢,减少了全身暴露,最大限度地减少了不良反应。在香烟烟雾和LPS诱导的COPD大鼠模型中,P29可显著改善肺功能,抑制炎症细胞活性,减少炎症细胞因子的释放,改善肺组织损伤。总的来说,我们的数据强调了P29在COPD中的治疗潜力。
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引用次数: 0
Cyclic Diguanylate G-Quadruplex Inducer–Siderophore Hybrids as Bifunctional Antibiofilm Agents against Pseudomonas aeruginosa 环双胍酯g -四重诱导剂-铁载体杂种作为铜绿假单胞菌双功能抗菌膜剂
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-04 DOI: 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}
引用次数: 0
Discovery of Novel, Potent, and Selective IRAK1 Inhibitors as Potential Therapeutics for Hepatocellular Carcinoma 发现新的、有效的、选择性的IRAK1抑制剂作为肝细胞癌的潜在治疗药物
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-04 DOI: 10.1021/acs.jmedchem.5c02988
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
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.
白细胞介素-1受体相关激酶1 (IRAK1)是toll样受体(TLR)/白细胞介素-1受体(IL-1R)信号传导的重要介质,其异常激活与包括肝细胞癌(HCC)在内的多种癌症的发病有关。然而,临床IRAK1抑制剂的开发一直受到其他激酶缺乏足够选择性的阻碍。在此,我们报告了一种新的IRAK1抑制剂A34的发现,通过基于结构的虚拟筛选和结构优化鉴定。A34有效抑制IRAK1, IC50值为10.6 nM,并对其他215种激酶(特别是IRAK4)表现出卓越的选择性。此外,A34在体内和体外均表现出显著的抗HCC活性,使其成为一种有价值的IRAK1化学探针,也是治疗HCC的潜在先导候选物。
{"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}
引用次数: 0
MTEGDRP: Interpretable Molecular Self-Attention Transformer and Equivariant Graph Neural Network Based on Multi-Omics Fusion for Drug Response Prediction in Cancer Cell Lines MTEGDRP:基于多组学融合的可解释分子自关注转换器和等变图神经网络用于肿瘤细胞系药物反应预测
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-04 DOI: 10.1021/acs.jmedchem.5c03438
Zhihan Liu,Kairui Lyu,Ya Li,Xinghui Sun,Xin Gao,Bin Yu
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.
癌症药物反应预测对精准医疗至关重要,因为它可以改善治疗效果并降低医疗成本。然而,现有的模型往往忽略了药物分子的几何特征及其与癌细胞的相互作用。为了解决这个问题,本研究提出了一个名为MTEGDRP的多组学融合模型。该模型使用变压器从药物和细胞数据中提取高级特征,以及它们之间的相互作用,而等变图神经网络捕获药物的空间结构。在回归任务中,MTEGDRP比目前最先进的方法表现得更好。消融研究表明,多组学整合和分子空间信息是有效的。特征权重的可视化为模型提供了可解释性。由于其良好的预测性能,MTEGDRP在指导精准医学抗癌药物设计方面显示出巨大的潜力。
{"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}
引用次数: 0
Do Amino-Oxetanes Resemble Amides? A Matched Molecular Pairs Property and Structural Comparison 氨基-氧烷与酰胺相似吗?一种匹配分子对性质及结构比较
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-04 DOI: 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.
氧乙烷显示出与酮羰基相当的性质,并越来越多地作为生物同分酯被探索。然而,这种比较是否适用于最常见的羰基衍生物:氨基氧烷与酰胺相似吗?在这里,我们提出了一个匹配的分子对研究12 3-芳基-3-氨基-氧乙烷和苯酰胺匹配的分子对,以评估它们作为同位异构体的活力。在调查的物理化学性质(pH稳定性、溶解度、亲脂性、清除率、渗透性)中,氨基氧烷与酰胺类化合物表现出广泛的可比性。氨基氧烷保持了类似酰胺的氢键受体和氢键给体的能力。这些发现支持了氨基氧烷作为酰胺替代品的潜力。然而,晶体结构分析强调了构象差异和通过引入氧烷环可获得的替代出口向量。间扭构象使氨基氧烷的扭转角和出口向量与磺胺更相似,因此具有更好的同类拓扑替代。总的来说,氨基氧烷提供了一个有吸引力的设计选择来调节物理化学性质和化学拓扑结构。
{"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}
引用次数: 0
Enhancement of Potency and Selectivity of 2-Aminoquinoline-Based Human Neuronal Nitric Oxide Synthase Inhibitors 2-氨基喹啉类人神经元型一氧化氮合酶抑制剂的效价和选择性增强
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2026-02-04 DOI: 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.
神经元一氧化氮合酶(nNOS)是神经退行性疾病和黑色素瘤的关键酶,是重要的治疗靶点。我们之前报道了基于2-氨基喹啉的nNOS抑制剂具有良好的活性,但受到次优效价、异构体选择性和脱靶效应的限制。为了解决这些问题,我们设计并合成了一系列新的7-芳基-6-氟-4-甲基-2-氨基喹啉衍生物。化合物16对人nNOS (Ki 16 nM)表现出极好的抑制作用,对人内皮NOS (eNOS)和人诱导NOS (iNOS)的选择性分别为~ 1800倍和~ 2900倍。PAMPA-BBB实验显示其具有较高的有效通透性(Pe = 13.04 × 10-6 cm/s),具有较强的中枢神经系统药物潜力。小鼠体内药代动力学研究进一步证明了持续的全身暴露、低清除率和强大的脑穿透性。而16的N-Me类似物化合物24则无活性。分子动力学模拟表明,n -甲基化破坏了尾部氨基的有利溶剂化,可能导致其活性和nNOS亲和力的丧失。
{"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}
引用次数: 0
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Journal of Medicinal Chemistry
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