ACS Medicinal Chemistry Letters最新文献

Next Generation NMR Flow Tube Optimized for Small Volume NMR Reaction Monitoring in Preclinical Drug Discovery 新一代核磁共振流管优化小体积核磁共振反应监测在临床前药物发现

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-21 DOI: 10.1021/acsmedchemlett.6c00388

Kathleen A. Farley, David Foley, Robert Krull, Martin Hoffman, Anna Codina, Peter Dorff, Christopher W. am Ende, Ormacinda White, Stephen W. Wright

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Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors 三环系列cns渗透CD38小分子抑制剂的设计与探索

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-10 DOI: 10.1021/acsmedchemlett.6c00301

Timothy R. Hodges, Youngjin Jang, Katerina Korch, Augustine Osuma, John T. Randolph, Reza Shiroodi, Benjamin D. Bergstrom, Chris Brosey, Purvi Jejurkar, Michael M. Sheehan, Renee N. Sadowski, Kelsey A. Lin, Jordan W. Brown, Anand Balakrishnan, Ioanna Zoi, Lance Bigelow, Rinku Jain, Noah P. Bradley, Alex Chapman, Alla Korepanova, Andrew M. Swensen, Madhurima Benekareddy, J. Brad Shotwell

{"title":"Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors","authors":"Timothy R. Hodges, Youngjin Jang, Katerina Korch, Augustine Osuma, John T. Randolph, Reza Shiroodi, Benjamin D. Bergstrom, Chris Brosey, Purvi Jejurkar, Michael M. Sheehan, Renee N. Sadowski, Kelsey A. Lin, Jordan W. Brown, Anand Balakrishnan, Ioanna Zoi, Lance Bigelow, Rinku Jain, Noah P. Bradley, Alex Chapman, Alla Korepanova, Andrew M. Swensen, Madhurima Benekareddy, J. Brad Shotwell","doi":"10.1021/acsmedchemlett.6c00301","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00301","url":null,"abstract":"Cluster of Differentiation 38 (CD38) plays a key rolein NAD+ metabolism and calcium signaling, and recent reportshighlighttherapeutic opportunities for CD38 modulation in central nervous system(CNS) disorders. In this report, we describe the rational design,synthesis, and exploration of structure–activity relationships(SAR) for a novel and brain-penetrant series of tricyclic compoundsthat form an adduct with ADPR to inhibit CD38 in an uncompetitivemanner. Rigidification of the bioactive conformation via covalenttethering of a 6-membered heteroaromatic core to an imidazole warheadserved as the key design element that afforded improved biochemicalpotency against both mouse and human CD38. Incremental property-basedoptimization of core and linker motifs generated analogues with enhancedunbound brain-to-plasma ratios in mice. These efforts led to the discoveryof brain-penetrant CD38 inhibitor 16, which was evaluatedin vivo and demonstrated dose-dependent increases of NAD+ measured in mouse brain and lung tissue samples following oral dosesranging from 3 to 100 mg/kg.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2160–2167"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124688","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}

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Novel Sulfur-Containing Heterocycloalkyl Substituted Bicyclic Compounds as Viral DNA Polymerase Inhibitors for Treating Viral Infections, in particular, Herpesvirus Infections 新型含硫杂环烷基取代双环化合物作为病毒DNA聚合酶抑制剂治疗病毒感染，特别是疱疹病毒感染

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-17 DOI: 10.1021/acsmedchemlett.6c00478

Ram W. Sabnis

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Toward Tumor-Conditional Release of Histone Deacetylase Inhibitors from Nongenotoxic Drug Conjugates 非基因毒性药物偶联物中组蛋白去乙酰化酶抑制剂的肿瘤条件释放

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-18 DOI: 10.1021/acsmedchemlett.6c00312

Ryan K. Muir, Ryan Gonciarz, Veronica Steri, Brian R. Blank, Byron Hahn, Adam R. Renslo

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Fluorinated 4-Methylideneisoxazolidin-5-ones: Synthesis and Apoptosis-Inducing Antiproliferative Activity 氟化4-甲基二恶唑烷-5- 1：合成及诱导细胞凋亡的抗增殖活性

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-25 DOI: 10.1021/acsmedchemlett.6c00344

Zi-Han Li, Ya Han, Yi-Chao Li, Xue-Qiong Zhang, Subarna Jyoti Kalita, Yi-Yong Huang

{"title":"Fluorinated 4-Methylideneisoxazolidin-5-ones: Synthesis and Apoptosis-Inducing Antiproliferative Activity","authors":"Zi-Han Li, Ya Han, Yi-Chao Li, Xue-Qiong Zhang, Subarna Jyoti Kalita, Yi-Yong Huang","doi":"10.1021/acsmedchemlett.6c00344","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00344","url":null,"abstract":"Sesquiterpene lactones, featuring an α-methylene-γ-lactonemoiety, serve as lead compounds for anticancer drug development. Theirnitrogen-containing analogues, namely, 4-methylideneisoxazolidin-5-ones,have attracted special attention for their promising anticancer properties.Installing a fluorine atom at the exocyclic double bond of these analoguesis highly desirable for improving metabolic stability, bioavailability,and lipophilicity, yet this has not been achieved to date due to thelack of an efficient synthetic method, representing a major obstaclein drug development. Herein, we report a Ni(II)-catalyzed [3 + 2]cycloaddition/rearrangement cascade reaction of gem-difluorocyclopropenyl imides and N-Bn nitrones,providing direct access to (Z)-4-(monofluoroalkylidene)isoxazolidin-5-onesin good to high yields. The compounds 3aw and 3as show promising in vitro antiproliferative activityagainst mouse mammary carcinoma 4T1 cells (IC50 = 6.85± 0.43 μM) and human lung carcinoma A549 cells (IC50 = 10.34 ± 0.07 μM), respectively. Mechanisticstudies reveal that the activity occurs via a mitochondria-mediatedintrinsic apoptotic pathway.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2219–2229"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124674","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}

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In This Issue, Volume 17, Issue 10 本刊第17卷第10期

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 DOI: 10.1021/acsmedchemlett.6c00502

Sophia L. Shevick

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Toward Rational Design of Orally Bioavailable PROTACs: Development of a Fully Computational Oral Absorption Score 面向口服生物利用度PROTACs的合理设计：一个完全计算的口服吸收评分的发展

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-17 DOI: 10.1021/acsmedchemlett.6c00305

Arman Fathizadeh, Erika M. V. Araujo, Nicholas T. Cockroft, Brett R. Beno, Keith R. Hornberger

{"title":"Toward Rational Design of Orally Bioavailable PROTACs: Development of a Fully Computational Oral Absorption Score","authors":"Arman Fathizadeh, Erika M. V. Araujo, Nicholas T. Cockroft, Brett R. Beno, Keith R. Hornberger","doi":"10.1021/acsmedchemlett.6c00305","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00305","url":null,"abstract":"Achieving adequate oral absorption for proteolysis-targetingchimeras(PROTACs) remains challenging due to their size, polarity, and conformationalcomplexity. While existing approaches often rely on physicochemicalproperty space or chameleonicity-driven models, a generalizable frameworkfor guiding compound design prior to synthesis is lacking. Here, weintroduce comPASS, a fully computational scoring function derivedfrom molecular dynamics-based descriptors that is designed to capturethe balance between molecular extension and exposed polarity throughnormalized radius of gyration and three-dimensional polar surfacearea of PROTACs. Across mouse and rat data sets, comPASS shows consistentpredictive performance and may facilitate prioritization of compoundsat early design stages. We further show that within the data setsstudied, extended molecular geometries are associated with improvedabsorption, when increased elongation is not driven solely by increasesin molecular size. To assess the potential benefit of incorporatingexperimental information, we also developed an enhanced variant, ePASS,which incorporates experimental polar surface area (EPSA) and lipophilicityterms consistent with prior approaches and shows promising predictiveperformance relative to similar literature methods. Together, theseresults establish practical guidance for presynthetic prioritizationof PROTACs and provide a potential framework for guiding the designof orally absorbed PROTACs.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2168–2174"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124754","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

Albumin-Binding Moieties Tune the Pharmacokinetics and Tumor Uptake of 177Lu-Labeled GRPR Radioligands 白蛋白结合部分调节177lu标记的GRPR放射配体的药代动力学和肿瘤摄取

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-04 DOI: 10.1021/acsmedchemlett.6c00338

Karim Obeid, Esther Olaniran Håkansson, Ekaterina Bezverkhniaia, Bobo Skillinghaug, Ulrika Rosenström, Panagiotis Kanellopoulos, Anna Orlova, Luke R. Odell

{"title":"Albumin-Binding Moieties Tune the Pharmacokinetics and Tumor Uptake of 177Lu-Labeled GRPR Radioligands","authors":"Karim Obeid, Esther Olaniran Håkansson, Ekaterina Bezverkhniaia, Bobo Skillinghaug, Ulrika Rosenström, Panagiotis Kanellopoulos, Anna Orlova, Luke R. Odell","doi":"10.1021/acsmedchemlett.6c00338","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00338","url":null,"abstract":"Although the gastrin-releasingpeptide receptor (GRPR)is an establishedtheranostic target across multiple cancers, many GRPR-targeting peptidesundergo rapid renal clearance, limiting tumor uptake and therapeuticexposure. Albumin-binding moieties (ABMs) reversibly interact withserum albumin, prolonging systemic exposure and increasing the opportunityfor tumor uptake. To examine how ABM structure and placement affectthis behavior, we prepared four DOTA-functionalized GRPR-targetingconjugates, varying both ABM lipophilicity and position relative tothe DOTA chelator. The conjugates were radiolabeled with lutetium-177in radiochemical yields and purities of >98%. All radioconjugatesretained GRPR-mediated uptake in PC-3 cells, exhibited subnanomolarreceptor affinity and enhanced blood retention. [177Lu]Lu-CA6356,bearing a 4-(p-iodophenyl)butyric acid-derived ABM,achieved the highest tumor uptake in PC-3 xenografts at 4 h pi (12± 2% IA/g), which increased by approximately 30% 24 h pi. Thesefindings show that ABM identity and placement can modulate systemicexposure and tumor uptake in GRPR-targeting radioligands.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2211–2218"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124873","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

Targeting Latent Tuberculosis Using Hypoxia-Activated Prodrugs of Bedaquiline Analogues 低氧激活贝达喹啉类似物前药靶向潜伏性结核

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-03 DOI: 10.1021/acsmedchemlett.6c00238

Christine G. Kim, Michael P. Hay, Robert F. Anderson, Sisira Kumara, Scott G. Franzblau, Christopher B. Cooper, Jiney Jose, Peter J. Choi

{"title":"Targeting Latent Tuberculosis Using Hypoxia-Activated Prodrugs of Bedaquiline Analogues","authors":"Christine G. Kim, Michael P. Hay, Robert F. Anderson, Sisira Kumara, Scott G. Franzblau, Christopher B. Cooper, Jiney Jose, Peter J. Choi","doi":"10.1021/acsmedchemlett.6c00238","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00238","url":null,"abstract":"The increasing emergenceof antimicrobial resistance (AMR) is reducingthe effectiveness of existing antibiotics against bacterial infections,including tuberculosis (TB), a deadly disease caused by Mycobacteriumtuberculosis (M.tb). Approximately 90% of infected individuals developlatent tuberculosis infection, for which current treatment optionsare limited. Latent tuberculosis infection is characterised by theformation of hypoxic granulomas, which restrict oxygen and drug penetration,highlighting the need for therapies effective under hypoxic conditions.In this study, a hypoxia-activated prodrug (HAP) strategy wasemployed to improve selective drug delivery of promising anti-tuberculosisdrugs bedaquiline, TBAJ-587 and TBAJ-876 (sorfequiline) to hypoxicTB granulomas. Thirty-six nitroimidazole-based hypoxia-activatedprodrugs (HAPs) were successfully synthesized and evaluated for antitubercularactivity. The HAPs exhibited potent in vitro activityunder both oxic and hypoxic conditions, with consistently lower MICvalues observed in the hypoxic assays. Assessment of hypoxic selectivitydemonstrated enhanced trigger cleavage under hypoxic conditions, providingstrong evidence for the hypoxia-selective activation of these compounds. Collectively, these findings highlight the therapeutic potentialof hypoxia-mediated strategies for the treatment of latent tuberculosis,particularly within hypoxic niches that drive disease persistenceand prolonged treatment regimens.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2140–2152"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130637","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

Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment 内酰胺桥接肽作为肾纤维化治疗白介素-11拮抗剂的研究进展

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 DOI: 10.1021/acsmedchemlett.6c00034

Xu Yang, Na Zhao, Ranran Zheng, Jian Li, Yujie Wu, Zhenxin Ma, Ningning Pang, Xin Meng, Ruirui Liu, Xiaochun Xiong, Chunmei An

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