ACS Medicinal Chemistry Letters最新文献_第8页

Novel 1H-Indole-3-carboxamide Derivatives as CDK4 Inhibitors for Treating Cancer 新型1h -吲哚-3-羧酸酰胺衍生物作为CDK4抑制剂治疗癌症

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-31 DOI: 10.1021/acsmedchemlett.6c00414

Ram W. Sabnis

引用次数: 0

Novel Compounds as SARS-CoV-2-Related 3C-Like Protease Inhibitors for Treating Coronavirus Infections 新型化合物作为sars - cov -2相关3c样蛋白酶抑制剂治疗冠状病毒感染

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-13 DOI: 10.1021/acsmedchemlett.6c00356

Ram W. Sabnis

引用次数: 0

Novel Compounds as SMARCA2 Inhibitors for Treating Non-small Cell Lung Cancer 新化合物作为SMARCA2抑制剂治疗非小细胞肺癌

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-08-03 DOI: 10.1021/acsmedchemlett.6c00413

Ram W. Sabnis

引用次数: 0

Irreversible NADH Cleavage by a Mitochondria-Targeted Metal-Free Photoredox Sensitizer with Activity in Cancer Cells 线粒体靶向无金属光氧化还原敏化剂在癌细胞中的不可逆NADH切割

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-02 DOI: 10.1021/acsmedchemlett.6c00205

Jean C. Neto, Eva Falomir, Juan F. Miravet, Francisco Galindo

{"title":"Irreversible NADH Cleavage by a Mitochondria-Targeted Metal-Free Photoredox Sensitizer with Activity in Cancer Cells","authors":"Jean C. Neto, Eva Falomir, Juan F. Miravet, Francisco Galindo","doi":"10.1021/acsmedchemlett.6c00205","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00205","url":null,"abstract":"Intracellular photoredoxcatalysis has emerged as an alternativeto classical photodynamic therapy, yet most systems promote reversibleNADH oxidation to NAD+. Here we show that the mitochondria-targeted,metal-free organic photosensitizer Cleav-1 induces photoinducedirreversible cleavage of NADH with nicotinamide release. Cleav-1 is accessible in two steps, highly fluorescent, photostable, andefficiently accumulates in mitochondria of MCF-7 breast cancer cells.In an aqueous solution, it catalyzes light-driven NADH consumption,and 1H NMR detects free nicotinamide, supporting cofactorcleavage rather than redox interconversion. Consistent with a photoredoxpathway, its first singlet excited state is efficiently quenched byNADH, whereas no singlet oxygen emission is observed. In cells, photoactivationof Cleav-1 causes marked photocytotoxicity (IC50 ∼ 300 nM), severe depletion of intracellular NAD, mitochondrialdysfunction, and predominantly apoptotic cell death. These resultssuggest irreversible nicotinamide cofactor damage as a distinct photobiologicalmechanism and highlight mitochondria-targeted organic photoredox sensitizersfor imaging-guided phototherapy.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1806–1815"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729412","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 Biophysical Characterization of Aminobenzo[d]isothiazole 1,1-Dioxide SOS1 Ligands 氨基苯并[d]异噻唑1,1-二氧化SOS1配体的结构与生物物理表征

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-03 DOI: 10.1021/acsmedchemlett.6c00300

Thiago Moreira Pereira, Atilio Reyes Romero, Marleen van der Laan, Guan Zhirui, Rick Oerlemans, Matthew Groves, Matteo Mori, Fiorella Meneghetti, Alexander Dömling

{"title":"Structural and Biophysical Characterization of Aminobenzo[d]isothiazole 1,1-Dioxide SOS1 Ligands","authors":"Thiago Moreira Pereira, Atilio Reyes Romero, Marleen van der Laan, Guan Zhirui, Rick Oerlemans, Matthew Groves, Matteo Mori, Fiorella Meneghetti, Alexander Dömling","doi":"10.1021/acsmedchemlett.6c00300","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00300","url":null,"abstract":"SOS1 is a guanine nucleotide exchange factor that promotesKRASactivation by catalyzing GDP release and GTP loading, making SOS1-mediatednucleotide exchange an attractive therapeutic target in KRAS-drivencancers. Herein, we report the synthesis, biophysical characterization,and structural analysis of aminobenzo[d]isothiazole1,1-dioxide SOS1 ligands. Compound 6f engaged SOS1 witha KD of 570 nM by microscale thermophoresis, supportedby surface plasmon resonance. X-ray crystal structures of SOS1 boundto compounds 6b and 6f refined previousbinding hypotheses regarding pocket engagement. Rather than beingdominated by sulfone-mediated contacts, SOS1 recognition is primarilydriven by hydrophobic and aromatic packing within the canonical pocket,a conserved ligand NH hydrogen bond to Asn879, and π-πstacking with Tyr884, recapitulating key features of BI-3406 binding.Comparative analysis further delineates vector requirements for productiveengagement of KRAS-facing regions, providing a structure-based frameworkfor future optimization of aminobenzo[d]isothiazole1,1-dioxide SOS1 ligands.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1895–1900"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729506","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 SARS-CoV-2-Related 3C-Like Protease Inhibitors for Treating Coronavirus Infections 新型化合物作为sars - cov -2相关3c样蛋白酶抑制剂治疗冠状病毒感染

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-31 DOI: 10.1021/acsmedchemlett.6c00397

Ram W. Sabnis

引用次数: 0

Novel Compounds as TREM2 Agonists for Treating Parkinson’s Disease, Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Nasu-Hakola Disease, and Stroke 新化合物作为TREM2激动剂治疗帕金森病、阿尔茨海默病、肌萎缩侧索硬化症、额颞叶痴呆、Nasu-Hakola病和中风

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-03 DOI: 10.1021/acsmedchemlett.6c00372

Ram W. Sabnis, Anika R. Sabnis

引用次数: 0

Structure- and Ligand-Based Discovery of Novel Non-Arginine-Based DDAH1 Inhibitors with Anti-Triple-Negative Breast Cancer Activity 基于结构和配体的新型非精氨酸DDAH1抑制剂抗三阴性乳腺癌活性的发现

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-10 DOI: 10.1021/acsmedchemlett.6c00143

Anthony J. Doman, Sara Tommasi, Jai Meyers, Julie-Ann Hulin, Arduino A. Mangoni, Michael V. Perkins, Pramod C. Nair

{"title":"Structure- and Ligand-Based Discovery of Novel Non-Arginine-Based DDAH1 Inhibitors with Anti-Triple-Negative Breast Cancer Activity","authors":"Anthony J. Doman, Sara Tommasi, Jai Meyers, Julie-Ann Hulin, Arduino A. Mangoni, Michael V. Perkins, Pramod C. Nair","doi":"10.1021/acsmedchemlett.6c00143","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00143","url":null,"abstract":"Dimethylarginine dimethylaminohydrolase 1 (DDAH1) regulatesnitricoxide (NO) synthesis, a key mediator of abnormal neovascularisation,i.e., vasculogenic mimicry, in triple negative breast cancer (TNBC).DDAH1 inhibitors have shown to suppress vasculogenic mimicry; however,they are mostly arginine-based and have limited bioavailability. Inthis study, we used ligand- and structure-based approaches to discovernovel nonarginine-based DDAH1 inhibitors. Computational screeningof over 1 million compounds led to the selection of 52 candidatesfor experimental testing, of which four showed more than 40% inhibitionof DDAH1, with two inhibitors, A8 and C8, having IC50 values below 180 μM. In triple-negativebreast cancer cells, A8 and C8 significantlysuppressed vasculogenic mimicry equivalent to previously known potentDDAH1 inhibitors. Molecular dynamics simulations of A8 in complex with DDAH1 demonstrate significant remodelling of thebinding pocket, leading to novel binding interactions with DDAH1 notobserved with previously reported inhibitors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1691–1698"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729676","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 5-HT2A Agonists for Treating Mental Illness or CNS Disorders 新化合物作为5-HT2A激动剂治疗精神疾病或中枢神经系统疾病

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-15 DOI: 10.1021/acsmedchemlett.6c00378

Ram W. Sabnis, Anika R. Sabnis

引用次数: 0

Lipophilic Ligand Efficiency-Monitored Discovery of Potent, Achiral, and Bioavailable Apo-IDO1 Inhibitors 亲脂配体效率-监测发现强效，非手性和生物可利用的载脂蛋白ido1抑制剂

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-07 DOI: 10.1021/acsmedchemlett.6c00252

Wieslaw M. Kazmierski, Nagaraju Miriyala, Martha De la Rosa, John Miller, Zachary O. Gentry, Vicente Samano, John Catalano, Pek Y. Chong, Feng Wang, Daniel J. Price, Jonathan Basilla, Makda Mebrahtu, Liping Wang, Lisa Shewchuk, Rosalie Matico, Richard Dunham

{"title":"Lipophilic Ligand Efficiency-Monitored Discovery of Potent, Achiral, and Bioavailable Apo-IDO1 Inhibitors","authors":"Wieslaw M. Kazmierski, Nagaraju Miriyala, Martha De la Rosa, John Miller, Zachary O. Gentry, Vicente Samano, John Catalano, Pek Y. Chong, Feng Wang, Daniel J. Price, Jonathan Basilla, Makda Mebrahtu, Liping Wang, Lisa Shewchuk, Rosalie Matico, Richard Dunham","doi":"10.1021/acsmedchemlett.6c00252","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00252","url":null,"abstract":"The indoleamine 2,3-dioxygenase 1 (IDO1) enzyme promotesan immunosuppressivemicroenvironment and disrupts natural antitumor immune response incancer cells. IDO1 inhibition has been a target of multiple cancerimmunotherapy efforts and is of interest to autoimmune and neurodegenerativedisease therapeutic areas. While the first-generation holo-IDO1 inhibitor,epacadostat, did not demonstrate sufficient response in the phaseIII ECHO-301 trial, multiple next-generation inhibitors and combinationtherapy clinical trials are ongoing. Herein, we describe our IDO1inhibitor discovery and optimization effort, in which the lipophilicligand efficiency index was used to track and guide drug-likeness,minimize entropic penalty, and deliver novel, potent, selective, andorally bioavailable apo-IDO1 inhibitors. Compounds in this class havethe potential for an improved pharmacodynamic response and thus arepotentially attractive clinical candidates. Our lead molecules areachiral and can be easily synthesized on a large scale in severalsynthetic steps.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1844–1853"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729556","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