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Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP.
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00517
Alexandria N Leveille, Thomas Schwarzrock, Hawley Brown, Bennett True, Joanet Plasencia, Philipp Neudecker, Alina Üffing, Oliver H Weiergräber, Dieter Willbold, Joshua A Kritzer
{"title":"Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP.","authors":"Alexandria N Leveille, Thomas Schwarzrock, Hawley Brown, Bennett True, Joanet Plasencia, Philipp Neudecker, Alina Üffing, Oliver H Weiergräber, Dieter Willbold, Joshua A Kritzer","doi":"10.1021/acsmedchemlett.4c00517","DOIUrl":"10.1021/acsmedchemlett.4c00517","url":null,"abstract":"<p><p>We report the first structure-activity studies of arylidene-indolinone compound <b>GW5074</b>, which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound, and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP. Eighteen analogs were synthesized and tested against both proteins. Inhibitory potencies were found to be in the mid- to high-micromolar range. 2D-NMR data revealed the binding site on GABARAP as hydrophobic pocket 1, where native peptide ligands bind with an aromatic side chain. Our results suggest that <b>GW5074</b> binds LC3B and GABARAP with micromolar affinity. These affinities could support further exploration in targeted protein degradation, but only if off-target effects and poor solubility can be appropriately addressed.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"271-277"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447387","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
Novel Tricyclic KRAS Inhibitors for the Treatment of Cancer
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 DOI: 10.1021/acsmedchemlett.4c0060910.1021/acsmedchemlett.4c00609
Taoqian Zhao,  and , Steven H. Liang*, 
{"title":"Novel Tricyclic KRAS Inhibitors for the Treatment of Cancer","authors":"Taoqian Zhao,&nbsp; and ,&nbsp;Steven H. Liang*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0060910.1021/acsmedchemlett.4c00609","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00609https://doi.org/10.1021/acsmedchemlett.4c00609","url":null,"abstract":"<p >The invention described in this patent application relates to oral compounds represented by Formula I. These compounds are designed to specifically target and inhibit KRAS alleles, providing both therapeutic and prophylactic potential in mammals, particularly for the treatment of KRAS-driven cancers.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"178–179 178–179"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394217","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
Addition to “The Death of the Strategy of Classical Chiral Switches Is an Exaggeration”
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 DOI: 10.1021/acsmedchemlett.4c0061310.1021/acsmedchemlett.4c00613
Israel Agranat*,  and , Ilaria D’Acquarica*, 
{"title":"Addition to “The Death of the Strategy of Classical Chiral Switches Is an Exaggeration”","authors":"Israel Agranat*,&nbsp; and ,&nbsp;Ilaria D’Acquarica*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0061310.1021/acsmedchemlett.4c00613","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00613https://doi.org/10.1021/acsmedchemlett.4c00613","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"344–346 344–346"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394225","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
Imaging Alpha-synuclein with Novel 5H-Imidazo[1,5-b][1,2,4]triazole Radioligands for the Diagnosis of Parkinson's Disease.
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00607
Zhendong Song, Steven H Liang
{"title":"Imaging Alpha-synuclein with Novel 5<i>H</i>-Imidazo[1,5-<i>b</i>][1,2,4]triazole Radioligands for the Diagnosis of Parkinson's Disease.","authors":"Zhendong Song, Steven H Liang","doi":"10.1021/acsmedchemlett.4c00607","DOIUrl":"10.1021/acsmedchemlett.4c00607","url":null,"abstract":"<p><p>The invention in this patent describes novel 5<i>H</i>-imidazo[1,5-<i>b</i>][1,2,4]triazole compounds, including radiolabeled derivatives, designed to target alpha-synuclein (α-syn). These compounds demonstrate potential as positron emission tomography (PET) radioligands for diagnosing α-syn-associated brain diseases, including Parkinson's disease.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"182-183"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447390","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
Cyclic Peptides Targeting Granzyme B: Potential Applications as PET Imaging Agents.
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00608
Qi-Long Hu, Steven H Liang
{"title":"Cyclic Peptides Targeting Granzyme B: Potential Applications as PET Imaging Agents.","authors":"Qi-Long Hu, Steven H Liang","doi":"10.1021/acsmedchemlett.4c00608","DOIUrl":"10.1021/acsmedchemlett.4c00608","url":null,"abstract":"<p><p>This patent application pertains to macrocyclic peptides and their radiolabeled derivatives, generally represented by Formula I. These compounds exhibit selective binding to Granzyme B (GzmB) and hold the potential for imaging disease or disorders associated with elevated GzmB levels. Such conditions include cancer immunotherapy, autoimmunity, wound healing, and inflammation.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"180-181"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447344","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
Novel Heterocyclic Piperazine Amide Derivatives as Alpha-synuclein PET Ligands for Diagnosis of Parkinson’s Disease
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 DOI: 10.1021/acsmedchemlett.4c0060610.1021/acsmedchemlett.4c00606
Yinlong Li,  and , Steven H. Liang*, 
{"title":"Novel Heterocyclic Piperazine Amide Derivatives as Alpha-synuclein PET Ligands for Diagnosis of Parkinson’s Disease","authors":"Yinlong Li,&nbsp; and ,&nbsp;Steven H. Liang*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0060610.1021/acsmedchemlett.4c00606","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00606https://doi.org/10.1021/acsmedchemlett.4c00606","url":null,"abstract":"<p >This Patent Highlight describes novel substituted heterocyclic piperazine amide compounds and their isotopically labeled derivatives. These compounds are designed as promising positron emission tomography (PET) ligands targeting alpha-synuclein, offering potential for the diagnosis of neurodegenerative disorders, including Parkinson’s disease.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"184–185 184–185"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394224","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 Heterocyclic Piperazine Amide Derivatives as Alpha-synuclein PET Ligands for Diagnosis of Parkinson's Disease.
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00606
Yinlong Li, Steven H Liang
{"title":"Novel Heterocyclic Piperazine Amide Derivatives as Alpha-synuclein PET Ligands for Diagnosis of Parkinson's Disease.","authors":"Yinlong Li, Steven H Liang","doi":"10.1021/acsmedchemlett.4c00606","DOIUrl":"10.1021/acsmedchemlett.4c00606","url":null,"abstract":"<p><p>This Patent Highlight describes novel substituted heterocyclic piperazine amide compounds and their isotopically labeled derivatives. These compounds are designed as promising positron emission tomography (PET) ligands targeting alpha-synuclein, offering potential for the diagnosis of neurodegenerative disorders, including Parkinson's disease.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"184-185"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447405","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
Cyclic Peptides Targeting Granzyme B: Potential Applications as PET Imaging Agents
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 DOI: 10.1021/acsmedchemlett.4c0060810.1021/acsmedchemlett.4c00608
Qi-Long Hu,  and , Steven H. Liang*, 
{"title":"Cyclic Peptides Targeting Granzyme B: Potential Applications as PET Imaging Agents","authors":"Qi-Long Hu,&nbsp; and ,&nbsp;Steven H. Liang*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0060810.1021/acsmedchemlett.4c00608","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00608https://doi.org/10.1021/acsmedchemlett.4c00608","url":null,"abstract":"<p >This patent application pertains to macrocyclic peptides and their radiolabeled derivatives, generally represented by Formula I. These compounds exhibit selective binding to Granzyme B (GzmB) and hold the potential for imaging disease or disorders associated with elevated GzmB levels. Such conditions include cancer immunotherapy, autoimmunity, wound healing, and inflammation.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"180–181 180–181"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394223","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 Tricyclic KRAS Inhibitors for the Treatment of Cancer.
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00609
Taoqian Zhao, Steven H Liang
{"title":"Novel Tricyclic KRAS Inhibitors for the Treatment of Cancer.","authors":"Taoqian Zhao, Steven H Liang","doi":"10.1021/acsmedchemlett.4c00609","DOIUrl":"10.1021/acsmedchemlett.4c00609","url":null,"abstract":"<p><p>The invention described in this patent application relates to oral compounds represented by Formula I. These compounds are designed to specifically target and inhibit KRAS alleles, providing both therapeutic and prophylactic potential in mammals, particularly for the treatment of KRAS-driven cancers.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"178-179"},"PeriodicalIF":3.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447414","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
Novel 3-Cycloaminoindole Compounds as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders.
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-01-04 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00615
Ram W Sabnis
{"title":"Novel 3-Cycloaminoindole Compounds as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders.","authors":"Ram W Sabnis","doi":"10.1021/acsmedchemlett.4c00615","DOIUrl":"10.1021/acsmedchemlett.4c00615","url":null,"abstract":"<p><p>Provided herein are novel 3-cycloaminoindole compounds as serotonergic psychedelic agents, pharmaceutical compositions, use of such compounds in treating psychosis, mental illness and central nervous system (CNS) disorders and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"190-191"},"PeriodicalIF":3.5,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447396","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
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