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Novel Bicyclic Heterocycles as MRGPRX2 Antagonists for Treating Inflammatory Diseases 新型双环杂环作为MRGPRX2拮抗剂治疗炎性疾病
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-04-02 DOI: 10.1021/acsmedchemlett.5c0016510.1021/acsmedchemlett.5c00165
Ram W. Sabnis*, 
{"title":"Novel Bicyclic Heterocycles as MRGPRX2 Antagonists for Treating Inflammatory Diseases","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c0016510.1021/acsmedchemlett.5c00165","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00165https://doi.org/10.1021/acsmedchemlett.5c00165","url":null,"abstract":"<p >Provided herein are novel bicyclic heterocycles as MRGPRX2 antagonists, pharmaceutical compositions, use of such compounds in treating inflammatory diseases, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"732–733 732–733"},"PeriodicalIF":3.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Novel Piperidinylpyridinylcarbonitrile Derivatives as QPCT and QPCTL Inhibitors for Treating Cancer 新型哌啶基吡啶基碳腈衍生物作为QPCT和QPCTL抑制剂治疗癌症
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-04-01 DOI: 10.1021/acsmedchemlett.5c0014210.1021/acsmedchemlett.5c00142
Ram W. Sabnis*, 
{"title":"Novel Piperidinylpyridinylcarbonitrile Derivatives as QPCT and QPCTL Inhibitors for Treating Cancer","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c0014210.1021/acsmedchemlett.5c00142","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00142https://doi.org/10.1021/acsmedchemlett.5c00142","url":null,"abstract":"<p >Provided herein are novel piperidinylpyridinylcarbonitrile derivatives as QPCT and QPCTL inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"540–541 540–541"},"PeriodicalIF":3.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Structural and Mechanistic Insights into Atypical Bacterial Topoisomerase Inhibitors 非典型细菌拓扑异构酶抑制剂的结构和机制研究
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-04-01 DOI: 10.1021/acsmedchemlett.5c0006010.1021/acsmedchemlett.5c00060
Paul D. Toth, Steven C. Ratigan, Joshua W. Powell, Sydney R. Cassel, Jack C. Yalowich, Craig A. McElroy, Steffen Lindert, Charles E. Bell and Mark J. Mitton-Fry*, 
{"title":"Structural and Mechanistic Insights into Atypical Bacterial Topoisomerase Inhibitors","authors":"Paul D. Toth,&nbsp;Steven C. Ratigan,&nbsp;Joshua W. Powell,&nbsp;Sydney R. Cassel,&nbsp;Jack C. Yalowich,&nbsp;Craig A. McElroy,&nbsp;Steffen Lindert,&nbsp;Charles E. Bell and Mark J. Mitton-Fry*,&nbsp;","doi":"10.1021/acsmedchemlett.5c0006010.1021/acsmedchemlett.5c00060","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00060https://doi.org/10.1021/acsmedchemlett.5c00060","url":null,"abstract":"<p >Novel bacterial topoisomerase inhibitors (NBTIs) targeting DNA gyrase and topoisomerase IV constitute a new antibacterial class for deadly pathogens such as MRSA. While most NBTIs induce gyrase-mediated single-strand DNA breaks, a subset of amide NBTIs induces both single-strand and double-strand DNA breaks. Here, we report the X-ray crystal structures of two such amide NBTIs, <b>148</b> and <b>185</b>, and demonstrate an unusual binding mode characterized by engagement of both GyrA D83 and R122. The synthesis of two isosteric triazole NBTIs is also described, one of which (<b>342</b>) affords only single-strand DNA breaks, while the other (<b>276</b>) also induces both single- and double-strand DNA breaks. A combination of docking and molecular dynamics simulations is employed to further investigate the potential structural underpinnings of differences in DNA cleavage.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"660–667 660–667"},"PeriodicalIF":3.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Novel Compounds as NLRP3 Inhibitors for Treating Asthma or COPD 新化合物作为NLRP3抑制剂治疗哮喘或COPD
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-04-01 DOI: 10.1021/acsmedchemlett.5c0014310.1021/acsmedchemlett.5c00143
Ram W. Sabnis*, 
{"title":"Novel Compounds as NLRP3 Inhibitors for Treating Asthma or COPD","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c0014310.1021/acsmedchemlett.5c00143","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00143https://doi.org/10.1021/acsmedchemlett.5c00143","url":null,"abstract":"<p >Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"538–539 538–539"},"PeriodicalIF":3.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Novel Compounds as NLRP3 Inhibitors for Treating Asthma or COPD. 新化合物作为NLRP3抑制剂治疗哮喘或COPD
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-04-01 eCollection Date: 2025-04-10 DOI: 10.1021/acsmedchemlett.5c00143
Ram W Sabnis
{"title":"Novel Compounds as NLRP3 Inhibitors for Treating Asthma or COPD.","authors":"Ram W Sabnis","doi":"10.1021/acsmedchemlett.5c00143","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00143","url":null,"abstract":"<p><p>Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"538-539"},"PeriodicalIF":3.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural and Mechanistic Insights into Atypical Bacterial Topoisomerase Inhibitors. 非典型细菌拓扑异构酶抑制剂的结构和机制研究。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-04-01 eCollection Date: 2025-04-10 DOI: 10.1021/acsmedchemlett.5c00060
Paul D Toth, Steven C Ratigan, Joshua W Powell, Sydney R Cassel, Jack C Yalowich, Craig A McElroy, Steffen Lindert, Charles E Bell, Mark J Mitton-Fry
{"title":"Structural and Mechanistic Insights into Atypical Bacterial Topoisomerase Inhibitors.","authors":"Paul D Toth, Steven C Ratigan, Joshua W Powell, Sydney R Cassel, Jack C Yalowich, Craig A McElroy, Steffen Lindert, Charles E Bell, Mark J Mitton-Fry","doi":"10.1021/acsmedchemlett.5c00060","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00060","url":null,"abstract":"<p><p>Novel bacterial topoisomerase inhibitors (NBTIs) targeting DNA gyrase and topoisomerase IV constitute a new antibacterial class for deadly pathogens such as MRSA. While most NBTIs induce gyrase-mediated single-strand DNA breaks, a subset of amide NBTIs induces both single-strand and double-strand DNA breaks. Here, we report the X-ray crystal structures of two such amide NBTIs, <b>148</b> and <b>185</b>, and demonstrate an unusual binding mode characterized by engagement of both GyrA D83 and R122. The synthesis of two isosteric triazole NBTIs is also described, one of which (<b>342</b>) affords only single-strand DNA breaks, while the other (<b>276</b>) also induces both single- and double-strand DNA breaks. A combination of docking and molecular dynamics simulations is employed to further investigate the potential structural underpinnings of differences in DNA cleavage.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"660-667"},"PeriodicalIF":3.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure-Based Optimization of TBK1 Inhibitors TBK1抑制剂的结构优化
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-03-31 DOI: 10.1021/acsmedchemlett.4c0063610.1021/acsmedchemlett.4c00636
Wenxuan Sun, Yuting Xie, Qiancheng Xia, Yuanxun Wang, Xiangbing Qi* and Niu Huang*, 
{"title":"Structure-Based Optimization of TBK1 Inhibitors","authors":"Wenxuan Sun,&nbsp;Yuting Xie,&nbsp;Qiancheng Xia,&nbsp;Yuanxun Wang,&nbsp;Xiangbing Qi* and Niu Huang*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0063610.1021/acsmedchemlett.4c00636","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00636https://doi.org/10.1021/acsmedchemlett.4c00636","url":null,"abstract":"<p >TBK1 is a crucial kinase involved in immunity, inflammation, and autophagy with dysregulation linked to various diseases, making it a potential therapeutic target. In this study, we applied a structure-based lead optimization approach to design potent and selective TBK1 inhibitors. A focused virtual library containing over 5,000 compounds was constructed, sampled, and refined within the kinase binding site, followed by a 10 ns molecular dynamics simulation for each modeled binding complex. Based on MM/PBSA binding free energies and structural clustering, we selected 14 structurally diverse compounds for chemical synthesis and biological assays. This strategy yielded a potent TBK1 inhibitor (IC<sub>50</sub> = 775 pM) from an initial hit of 19.57 μM. This inhibitor features a novel scaffold and exhibits excellent enzymatic inhibition. Furthermore, it enhances immune-mediated cytotoxicity without exhibiting cytotoxicity when used as a single agent. These findings provide a foundation for the development of targeted therapies for the treatment of TBK1-associated diseases.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"611–616 611–616"},"PeriodicalIF":3.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Patents: The Protectors of Intellectual Property-Importance of Patents in Drug Discovery. 专利：知识产权的保护者——专利在药物研发中的重要性。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-03-31 eCollection Date: 2025-04-10 DOI: 10.1021/acsmedchemlett.5c00130
Ahmed F Abdel-Magid
{"title":"Patents: The Protectors of Intellectual Property-Importance of Patents in Drug Discovery.","authors":"Ahmed F Abdel-Magid","doi":"10.1021/acsmedchemlett.5c00130","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00130","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"498-499"},"PeriodicalIF":3.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure-Based Optimization of TBK1 Inhibitors. TBK1抑制剂的结构优化
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-03-31 eCollection Date: 2025-04-10 DOI: 10.1021/acsmedchemlett.4c00636
Wenxuan Sun, Yuting Xie, Qiancheng Xia, Yuanxun Wang, Xiangbing Qi, Niu Huang
{"title":"Structure-Based Optimization of TBK1 Inhibitors.","authors":"Wenxuan Sun, Yuting Xie, Qiancheng Xia, Yuanxun Wang, Xiangbing Qi, Niu Huang","doi":"10.1021/acsmedchemlett.4c00636","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00636","url":null,"abstract":"<p><p>TBK1 is a crucial kinase involved in immunity, inflammation, and autophagy with dysregulation linked to various diseases, making it a potential therapeutic target. In this study, we applied a structure-based lead optimization approach to design potent and selective TBK1 inhibitors. A focused virtual library containing over 5,000 compounds was constructed, sampled, and refined within the kinase binding site, followed by a 10 ns molecular dynamics simulation for each modeled binding complex. Based on MM/PBSA binding free energies and structural clustering, we selected 14 structurally diverse compounds for chemical synthesis and biological assays. This strategy yielded a potent TBK1 inhibitor (IC<sub>50</sub> = 775 pM) from an initial hit of 19.57 μM. This inhibitor features a novel scaffold and exhibits excellent enzymatic inhibition. Furthermore, it enhances immune-mediated cytotoxicity without exhibiting cytotoxicity when used as a single agent. These findings provide a foundation for the development of targeted therapies for the treatment of TBK1-associated diseases.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"611-616"},"PeriodicalIF":3.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Patents: The Protectors of Intellectual Property─Importance of Patents in Drug Discovery 专利：知识产权的保护者──专利在药物研发中的重要性
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-03-31 DOI: 10.1021/acsmedchemlett.5c0013010.1021/acsmedchemlett.5c00130
Ahmed F. Abdel-Magid, 
{"title":"Patents: The Protectors of Intellectual Property─Importance of Patents in Drug Discovery","authors":"Ahmed F. Abdel-Magid,&nbsp;","doi":"10.1021/acsmedchemlett.5c0013010.1021/acsmedchemlett.5c00130","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00130https://doi.org/10.1021/acsmedchemlett.5c00130","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 4","pages":"498–499 498–499"},"PeriodicalIF":3.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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