Journal of Medicinal Chemistry最新文献_第4页

Modulatory Role of Pantropic Cell Signaling Pathways in the Antimigratory and Antiproliferative Action of Triazole Chelated Iridium(III) Complexes in Cervical Cancer Cells 三唑螯合铱（III）配合物在宫颈癌细胞抗移行和抗增殖作用中的泛细胞信号通路调节作用

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-11 DOI: 10.1021/acs.jmedchem.4c01997

Anushka Mondal, Bishnu Das, Souvik Karmakar, Soumili Pani, Shrabani Khan, Parna Gupta, Jayasri Das Sarma

{"title":"Modulatory Role of Pantropic Cell Signaling Pathways in the Antimigratory and Antiproliferative Action of Triazole Chelated Iridium(III) Complexes in Cervical Cancer Cells","authors":"Anushka Mondal, Bishnu Das, Souvik Karmakar, Soumili Pani, Shrabani Khan, Parna Gupta, Jayasri Das Sarma","doi":"10.1021/acs.jmedchem.4c01997","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01997","url":null,"abstract":"In the current study, the antimigratory and antiproliferative effect of three substituted triazole-chelated iridium(III) complexes Ir-TRN, Ir-TRH, and Ir-TRF were studied with special emphasis on modulation of P53 activity, a cell cycle regulator. ERK2/MAPK, another crucial cell signaling pathway protein, was also shown to play a crucial role in cell migration and proliferation. The complexes increase the ROS generation within the cell, further supporting apoptotic induction by exerting cellular oxidative stress. These metal complexes also affect ER stress by altering ERp29, an ER-resident chaperone, further inducing the process of apoptosis. The iridium(III) complexes restrict cervical cancer cell migration and proliferation by exerting pronounced effects as P53 activators and downregulation of ERK2/MAPK activity in cervical cancer cells. The underpinning mechanism of P53 and ERK2/MAPK activity in cervical cancer cells in the presence of iridium(III) complexes was studied in detail in this study, which paves the way for developing promising avenues for cancer therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599041","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 the First-in-Class Dual-Target ROCK/HDAC Inhibitor with Potent Antitumor Efficacy in Vivo That Trigger Antitumor Immunity 发现首个在体内具有强效抗肿瘤作用的 ROCK/HDAC 双靶点抑制剂，可触发抗肿瘤免疫力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-10 DOI: 10.1021/acs.jmedchem.4c02183

Churu Mao, Jiebin Fang, Shijie Zou, Yun Huang, Xiaoming Chen, Xia Ding, Zhangyun Fang, Ningjing Zhang, Yijie Lou, Zhe Chen, Wanjing Ding, Zhongjun Ma

引用次数: 0

Structure-Guided Design of Affinity/Covalent-Bond Dual-Driven Inhibitors Targeting the AMP Site of FBPase 以 FBPase 的 AMP 位点为目标的亲和力/共价键双驱动抑制剂的结构引导设计

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-09 DOI: 10.1021/acs.jmedchem.4c01886

Hongxuan Cao, Zeyue Huang, Zheng Liu, Xiao Zhang, Yanliang Ren, Muhammad Salman Hameed, Li Rao, Nokwanda P. Makunga, Georgi M. Dobrikov, Jian Wan

{"title":"Structure-Guided Design of Affinity/Covalent-Bond Dual-Driven Inhibitors Targeting the AMP Site of FBPase","authors":"Hongxuan Cao, Zeyue Huang, Zheng Liu, Xiao Zhang, Yanliang Ren, Muhammad Salman Hameed, Li Rao, Nokwanda P. Makunga, Georgi M. Dobrikov, Jian Wan","doi":"10.1021/acs.jmedchem.4c01886","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01886","url":null,"abstract":"Fructose-1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type II diabetes. FBPase inhibitors targeting the AMP allosteric site have been documented, but their limited selectivity has raised concerns about adverse effects. To address this issue, we designed the affinity/covalent-bond dual-driven inhibitors based on the pharmacophore knowledge of the AMP pocket and neighboring cysteine residue (C179) of FBPase using the cysteine-targeting reactivity warhead screen followed by a structural optimization strategy. Pull-down and Western Blotting assays confirmed FBPase as a direct target in hepatic cells. X-ray cocrystallographic structure of FBPase-11 and Cov_DOX calculation demonstrated that hydrogen bonding and π–π stacking were the predominant driving force for the inhibition of sulfonylurea-based FBPase covalent inhibitors, while covalent binding with C179 enhances the inhibitors’ long-lasting hypoglycemic effects. Together, this work highlights the potential of affinity/covalent-bond dual-driven inhibitors in drug development and provides a promising approach for developing potent drugs targeting AMP-associated proteins.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596900","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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Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy 发现用于癌症治疗的新型大环非共价 CDK7 抑制剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-09 DOI: 10.1021/acs.jmedchem.4c02098

Hongfu Lu, Yihong Zhang, Jinxin Liu, Tao Jiang, Xiang Yu, Haoyu Zhang, Tao Liang, Jingjing Peng, Xin Cai, Xiaoling Lan, Jinmin Ren, Mei Ge, Jingyang Zhang, Jingjin Shang, Jiaojiao Yu, Hongcan Ren, Qiang Liu, Jinting Gao, Lili Tang, Xiao Ding, Man Zhang, Alex Aliper, Qiang Lu, Fusheng Zhou, Jiong Lan, Feng Ren, Alex Zhavoronkov

{"title":"Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy","authors":"Hongfu Lu, Yihong Zhang, Jinxin Liu, Tao Jiang, Xiang Yu, Haoyu Zhang, Tao Liang, Jingjing Peng, Xin Cai, Xiaoling Lan, Jinmin Ren, Mei Ge, Jingyang Zhang, Jingjin Shang, Jiaojiao Yu, Hongcan Ren, Qiang Liu, Jinting Gao, Lili Tang, Xiao Ding, Man Zhang, Alex Aliper, Qiang Lu, Fusheng Zhou, Jiong Lan, Feng Ren, Alex Zhavoronkov","doi":"10.1021/acs.jmedchem.4c02098","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02098","url":null,"abstract":"Cyclin-dependent kinase 7 (CDK7) is a key regulator of the cell cycle and transcription, making it a promising target for cancer therapy. Although current CDK7 inhibitors have improved in their selectivity and druglike properties, CDK7 inhibitors have failed to progress through clinical development due to severe gastrointestinal and hematotoxic side effects. To mitigate these limitations, we have developed novel, macrocyclic, noncovalent CDK7 hit compounds 2 and 3 using a macrocyclization platform that has optimized these compounds from SY-5609, a leading clinical asset. We conducted extensive structure–activity relationship (SAR) studies to improve their potency, enhance oral bioavailability, and reduce intestinal distribution, which resulted in compound 13. Compound 13 exhibits potent in vitro activity, good ADME properties, and robust in vivo antitumor activity in xenograft models as a monotherapy. Notably, compound 13 with lower basicity demonstrated improved Caco-2 permeability, reduced blood/plasma ratio, and reduced intestinal distribution in rats, thus mitigating gastrointestinal and hematotoxic side effects.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597285","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

Recent Progress and Future Perspectives on Anti-Hyperuricemic Agents 抗高尿酸血症药物的最新进展和未来展望

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-08 DOI: 10.1021/acs.jmedchem.4c01260

Zhiqiang Sun, Xuewen Zhang, Zean Zhao, Xiaoxun Li, Jianxin Pang, Jianjun Chen

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A Fast Method to Monitor Tyrosine Kinase Inhibitor Mechanisms 监测酪氨酸激酶抑制剂机制的快速方法

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-08 DOI: 10.1021/acs.jmedchem.4c02042

Alejandro Fernández, Margarida Gairí, María Teresa González, Miquel Pons

引用次数: 0

Structure–Activity Relationships and Discovery of (S)-5-(tert-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2′,1′:2,3]imidazo[4,5-h]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-Centric HBV RNA Destabilizer (S)-5-(叔丁基)-11-(二氟甲氧基)-9-甲氧基-2-氧代-1,2,5,6-四氢吡啶并[2′,1′:2,3]咪唑并[4,5-h]喹啉-3-羧酸 (AB-161) 的结构-活性关系及发现，一种新型口服且以肝脏为中心的 HBV RNA 破坏剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-08 DOI: 10.1021/acs.jmedchem.4c01928

Dimitar Gotchev, Shuai Chen, Benjamin Dugan, Bruce D. Dorsey, Xu Wang, Muhammad Sheraz, Rose Kowalski, Fei Liu, Sunny Tang, Tim Chiu, Troy Harasym, Ingrid E. Graves, Emily P. Thi, Jeremy D. Mason, Nathan Overholt, Ravi Dugyala, Angela M. Lam, Andrew G. Cole, Michael J. Sofia

{"title":"Structure–Activity Relationships and Discovery of (S)-5-(tert-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2′,1′:2,3]imidazo[4,5-h]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-Centric HBV RNA Destabilizer","authors":"Dimitar Gotchev, Shuai Chen, Benjamin Dugan, Bruce D. Dorsey, Xu Wang, Muhammad Sheraz, Rose Kowalski, Fei Liu, Sunny Tang, Tim Chiu, Troy Harasym, Ingrid E. Graves, Emily P. Thi, Jeremy D. Mason, Nathan Overholt, Ravi Dugyala, Angela M. Lam, Andrew G. Cole, Michael J. Sofia","doi":"10.1021/acs.jmedchem.4c01928","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01928","url":null,"abstract":"Lowering hepatitis B surface antigen (HBsAg) levels from covalently closed circular DNA (cccDNA) and the integrated genome could reduce the persistence of hepatitis B virus (HBV) infection. Since HBV replication occurs in the liver and to ameliorate the peripheral neuropathy observed with a first-generation tricyclic 4-pyridone PAPD5/7 inhibitor (AB-452) having high systemic exposure, we focused on increasing the hepatocyte concentration and reducing plasma levels. Optimization of a novel series of PAPD5/7 inhibitors that decrease HBsAg levels led to the tetracyclic 2-pyridone AB-161, which was similarly potent to AB-452 in vitro and in vivo but showed dramatically higher rodent liver-to-plasma ratios. There were no neurobehavioral effects with AB-161 in dogs up to 45 mg/kg after 60 days, unlike with AB-452, where these were observed at lower doses by day 14. AB-161 was then advanced into 90-day GLP toxicology studies, where the improved neurotoxicity profile persisted, but reproductive issues emerged, leading to discontinuation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596899","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

Closing the Design–Make–Test–Analyze Loop: Interplay between Experiments and Predictions Drives PROTACs Bioavailability 关闭 "设计-制造-测试-分析 "循环：实验与预测的相互作用推动了 PROTACs 生物利用率的提高

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-08 DOI: 10.1021/acs.jmedchem.4c01642

Zulma Santisteban Valencia, Jennifer Kingston, Filip Miljković, Hannah Rowbottom, Nadia Mann, Sophie Davies, Martin Ekblad, Silvio Di Castro, Karolina Kwapień, Erik Malmerberg, Stig D. Friis, Thomas Lundbäck, Tomas Leek, Johan Wernevik

{"title":"Closing the Design–Make–Test–Analyze Loop: Interplay between Experiments and Predictions Drives PROTACs Bioavailability","authors":"Zulma Santisteban Valencia, Jennifer Kingston, Filip Miljković, Hannah Rowbottom, Nadia Mann, Sophie Davies, Martin Ekblad, Silvio Di Castro, Karolina Kwapień, Erik Malmerberg, Stig D. Friis, Thomas Lundbäck, Tomas Leek, Johan Wernevik","doi":"10.1021/acs.jmedchem.4c01642","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01642","url":null,"abstract":"The drug development landscape is expanding to include drug modalities such as PROteolysis-TArgeting Chimeras (PROTACs) and peptides, offering possibilities for previously intractable biological targets. However, with their size and chemical nature, they diverge from established frameworks for the prediction of oral bioavailability. This evolution to larger and more complex molecules necessitates new methodologies and prediction models to continuously expand on bioavailability guidelines. We describe the high-capacity adoption of two chromatographic physicochemical assays and their application for iterative compound optimization to achieve oral bioavailability. We further describe how these data underpin the continuous refinement of internal machine learning models, which guide compound synthesis decisions in the molecular design phase. Based on data for a set of 691 PROTACs, and two project examples, we confirm a sweet spot for oral bioavailability at log D values higher than the norm for small molecules and show how experimental data and prediction models synergize to effectively drive chemistry optimization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596896","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 Thiazole Carboxamides as Novel Vanin-1 Inhibitors for Inflammatory Bowel Disease Treatment 发现治疗炎症性肠病的新型 Vanin-1 抑制剂噻唑羧酰胺类化合物

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-08 DOI: 10.1021/acs.jmedchem.4c01838

Tao Xie, Gao-Yao Cao, Shize Zhang, Meng-Ke Li, Xin Jin, Liu Liu, Guangji Wang, Le Zhen

{"title":"Discovery of Thiazole Carboxamides as Novel Vanin-1 Inhibitors for Inflammatory Bowel Disease Treatment","authors":"Tao Xie, Gao-Yao Cao, Shize Zhang, Meng-Ke Li, Xin Jin, Liu Liu, Guangji Wang, Le Zhen","doi":"10.1021/acs.jmedchem.4c01838","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01838","url":null,"abstract":"Inflammatory bowel disease (IBD) is a clinically heterogeneous disease demanding more therapeutic targets and intervention strategies. Vanin-1, an oxidative stress-regulating protein, has emerged as a promising target for alleviating inflammation and oxidative stress. In this study, a series of thiazole carboxamide derivatives as vanin-1 inhibitors were designed and synthesized. The preferred compound, X17, demonstrated potent inhibition against vanin-1 at the protein, HT-29 cell, and tissue levels, whose binding mode with the target was confirmed via the cocrystal structure. X17 achieved a high bioavailability of 81% in rats, accompanied by concentration-dependent inhibition of serum vanin-1. In a DSS-induced mouse colitis model, X17 exhibited potent anti-inflammatory and antioxidant activities, repressing the inflammatory factor expressions and myeloperoxidase activity, elevating the colonic glutathione reserve, and restoring the intestinal barrier. Collectively, these findings depict the discovery of a potent vanin-1 inhibitor, providing an opportunity for further drug candidate development for treating IBD.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598083","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 SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression 发现 SD-436：一种强效、高选择性和高效的 STAT3 PROTAC 降解剂，可实现肿瘤的完全和长期消退

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-07 DOI: 10.1021/acs.jmedchem.4c01946

Renqi Xu, Haibin Zhou, Longchuan Bai, Donna McEachern, Dimin Wu, Ranjan Kumar Acharyya, Mi Wang, Jelena Tošović, Chao-Yie Yang, Krishnapriya Chinnaswamy, Jennifer L. Meagher, Jeanne A. Stuckey, Cai Liu, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang

{"title":"Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression","authors":"Renqi Xu, Haibin Zhou, Longchuan Bai, Donna McEachern, Dimin Wu, Ranjan Kumar Acharyya, Mi Wang, Jelena Tošović, Chao-Yie Yang, Krishnapriya Chinnaswamy, Jennifer L. Meagher, Jeanne A. Stuckey, Cai Liu, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang","doi":"10.1021/acs.jmedchem.4c01946","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01946","url":null,"abstract":"STAT3 is an attractive therapeutic target for cancer and other human diseases. We have previously reported the discovery of potent, selective, and efficacious PROTAC STAT3 degraders SD-36 and SD-91. In this study, we have designed and synthesized a novel series of STAT3 degraders using a new, high-affinity STAT3 ligand with excellent chemical stability and cereblon ligands. Our efforts led to the discovery of SD-436, a highly potent and selective STAT3 degrader. A single intravenous administration of SD-436 at 5 mg/kg effectively induces rapid, complete, and durable depletion of STAT3 in mouse native and xenograft tumor tissues. SD-436 achieves complete and long-lasting tumor regression even with a weekly dosing schedule in leukemia and lymphoma xenograft models in mice. SD-436 represents a promising STAT3 degrader for advanced preclinical development as a new therapy for the treatment of human cancers and other human diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596893","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