ACS Medicinal Chemistry Letters最新文献

{"title":"Structural and Molecular Insight into the PWWP1 Domain of NSD2 from the Discovery of Novel Binders Via DNA-Encoded Library Screening","authors":"Gavin W. Collie*,&nbsp;Bryony Ackroyd,&nbsp;Catriona Corbishley,&nbsp;Daniel H. O’Donovan,&nbsp;Alex Edwards,&nbsp;Andrea Gohlke,&nbsp;Xiaoxiao Guo,&nbsp;Bethan Howells,&nbsp;Yuliang Li,&nbsp;Andrew Madin,&nbsp;Alexander G. Milbradt,&nbsp;Emma L. Rivers*,&nbsp;Sandeep K. Talapatra,&nbsp;Elizabeth Underwood and Alice Webb,&nbsp;","doi":"10.1021/acsmedchemlett.5c00396","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00396","url":null,"abstract":"<p >NSD2 is a key epigenetic regulator and has received considerable attention as a drug target due to its well-documented role in tumorigenesis. We report here a DNA-encoded library screen targeting the PWWP1 domain of NSD2 from which we discovered novel, potent, and selective binders. Furthermore, these compounds were used to develop a novel crystal system, increasing our understanding of the folding of this domain. Together, these results provide a solid molecular and structural basis for the further study of the PWWP1 domain of NSD2 as a cancer drug target.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1703–1708"},"PeriodicalIF":4.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00396","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036652","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}

{"title":"Novel Serotonergic Psychedelic Agents as 5-HT2A Agonists for Treating Psychosis, Mental Illness, and CNS Disorders","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00484","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00484","url":null,"abstract":"<p >Provided herein are novel serotonergic psychedelic agents as 5-HT2A agonists, 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 9","pages":"1729–1730"},"PeriodicalIF":4.0,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036620","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}

{"title":"Optimization of Quinazolines for Inhibition of Trypanosoma brucei Proliferation","authors":"Sam Spijkers-Shaw,&nbsp;Pradip K. Gadekar,&nbsp;Baljinder Singh,&nbsp;Gaurav Kumar,&nbsp;Amrita Sharma,&nbsp;Benjamin Hoffman,&nbsp;Michael P. Pollastri,&nbsp;Kojo Mensa-Wilmot and Lori Ferrins*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00374","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00374","url":null,"abstract":"<p >A large population of people remain at risk of contracting human African trypanosomiasis (HAT), which has significant health implications and leads to death. To prepare for future epidemics and provide alternative therapies in case of resistance to current treatment options for HAT, there is a need to continue developing novel therapeutics. Previously, we reported the repurposing and reoptimization of human kinase inhibitor, Lapatinib, toward inhibiting <i>Trypanosoma brucei</i> proliferation. These efforts improved the selectivity and potency; however, the physicochemical properties of derivatives such as <b>2</b> remained unsatisfactory. As such, here we report the further structural optimization of <b>2</b> to improve ADME properties and retain antitrypanosomal potency. Modifications at the 4- and 6-positions of the quinazoline core were systematically investigated to assess ADME properties and <i>T. brucei</i> inhibition. Combining the best substituents for antitrypanosomal potency and aqueous solubility led to the identification of compounds with significantly improved potency and metabolic stability.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1806–1813"},"PeriodicalIF":4.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00374","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036456","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}

{"title":"Synthesis and Evaluation of Diphenylpyrazine Cyclic Amine Derivatives as IP Receptor Agonists","authors":"Xianrong Cai*,&nbsp;Guoyi Lin,&nbsp;Juan Tang,&nbsp;Yuhe Wang,&nbsp;Juping Cheng,&nbsp;Guiying Liu,&nbsp;Qiang Wang,&nbsp;Chunru Cheng,&nbsp;Zhenqiang Mu,&nbsp;Pengjun Zhou,&nbsp;Qingquan Fu* and Xiaoli An*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00312","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00312","url":null,"abstract":"<p >Pulmonary arterial hypertension (PAH) is a severe, progressive condition with limited treatments. This study focuses on developing novel IP receptor agonists for PAH therapy. By modifying MRE-269, a highly selective IP receptor agonist, we designed and synthesized 2-cyclic amino-5,6-diphenylpyrazine derivatives. Systematic evaluation revealed that introducing a dimethyl group at the C3 position of the piperidine ring significantly improved antiaggregatory activity. The optimal compound <b>6c-14S</b> demonstrated a 40-fold increase in potency compared to MRE-269. Docking studies confirmed its high selectivity for the IP receptor, and pharmacokinetic studies showed a 3-fold improvement in half-life, suggesting its potential for therapeutic development.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1772–1779"},"PeriodicalIF":4.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036279","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}

{"title":"The New Paradigm in Pharma R&D","authors":"Charles H. Reynolds*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00469","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00469","url":null,"abstract":"<p >Drug discovery has seen dramatic change over the last 25 years. The vertically integrated large company model prevalent for more than 50 years has at least partly been replaced with a more distributed drug discovery enterprise that includes large numbers of small research organizations.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1690–1692"},"PeriodicalIF":4.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036386","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}

{"title":"Glycine Betaine-Functionalized Ionic Liquids: Design of Versatile Bioplatform for Incorporating Biologically Active Moieties into Cations","authors":"Witold Stachowiak,&nbsp;Marcin Wysocki,&nbsp;Lorenzo Guazzelli and Michał Niemczak*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00280","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00280","url":null,"abstract":"<p >We report a novel series of ILs formed by coupling glycine betaine with the biologically active herbicide MCPA via an ester bond. ILs were synthesized through a 2-step <i>O</i>-alkylation process, followed by product isolation using flash chromatography. The alkyl chain length between the carboxylic groups determines solubility and octanol–water partition coefficient, whereas the rate of their hydrolysis is highly influenced by the pH of aqueous solution. All compounds retained the biological activity of the incorporated herbicide.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1756–1761"},"PeriodicalIF":4.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00280","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036540","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}

{"title":"Prodrugs 2-(Phosphonomethyl)pentanedioic Acid (2-PMPA) as Orally Available Glutamate Carboxypeptidase II Inhibitors","authors":"Niyada Hin,&nbsp;Chae Bin Lee,&nbsp;Sadakatali Gori,&nbsp;Barbara S. Slusher,&nbsp;Rana Rais and Takashi Tsukamoto*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00384","DOIUrl":"10.1021/acsmedchemlett.5c00384","url":null,"abstract":"<p >2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is one of the most potent inhibitors of glutamate carboxypeptidase II (GCPII), a zinc metallopeptidase that cleaves glutamate from <i>N</i>-acetylaspartylglutamic acid and folylpoly-γ-glutamate. Due to the presence of multiple acidic groups, 2-PMPA exhibits poor oral bioavailability, limiting its therapeutic utility despite its potent GCPII inhibitory activity. One approach to address this challenge is to develop prodrugs of 2-PMPA with enhanced lipophilicity and improved oral absorption as demonstrated by tris-POC-2-PMPA and tetra-ODOL-2-PMPA. To expand the diversity of our prodrug strategy for 2-PMPA, we explored two promoieties for the phosphonate group of 2-PMPA, ProTide and cycloSal groups, while converting the two carboxylic acids to ester promoieties. The resulting prodrugs were assessed for their ability to deliver 2-PMPA in plasma in mice following oral administration. Among them, several cycloSal-based prodrugs delivered micromolar levels of 2-PMPA in plasma following oral administration, representing another effective prodrug strategy to orally deliver 2-PMPA.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1830–1834"},"PeriodicalIF":4.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935881","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}

{"title":"Radiosynthesis and Preclinical Evaluation of a Carbon-11 Labeled Phosphodiesterase 7 Inhibitor for PET Neuroimaging","authors":"Zhiwei Xiao,&nbsp;Jiyun Sun,&nbsp;Masayuki Fujinaga,&nbsp;Huiyi Wei,&nbsp;Chunyu Zhao,&nbsp;Achi Haider,&nbsp;Richard Van,&nbsp;Shi Kuang,&nbsp;Tomoteru Yamasaki,&nbsp;Yiding Zhang,&nbsp;Jian Rong,&nbsp;Kuan Hu,&nbsp;Jiahui Chen,&nbsp;Erick Calderon Leon,&nbsp;Wakana Mori,&nbsp;Lin Xie,&nbsp;Junjie Wei,&nbsp;Yi Xu,&nbsp;Yihan Shao,&nbsp;Han-Ting Zhang,&nbsp;Ying Xu,&nbsp;Chongzhao Ran,&nbsp;KC Kent Lloyd,&nbsp;Lu Wang,&nbsp;Ming-Rong Zhang* and Steven H. Liang*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00385","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00385","url":null,"abstract":"<p >Dysfunction of cyclic nucleotide phosphodiesterase 7 (PDE7) has been associated with excess intracellular cAMP concentrations, fueling pathogenic processes that are implicated in neurodegenerative disorders. This study aimed to develop a suitable positron emission tomography (PET) probe that allows noninvasive mapping of PDE7 in the mammalian brain. Based on a spiro cyclohexane-1,4′-quinazolinone scaffold with known inhibitory properties toward PDE7, we designed and synthesized a carbon-11 labeling tolerant methoxy analog. The resulting PET probe, code named [¹¹C]P7-2104 (<b>27</b>), was synthesized in high molar activities (170–220 GBq/μmol) with decay-corrected radiochemical yields of 34 ± 7%. <i>In vitro</i> cell uptake of [¹¹C]<b>27</b> was 6–7-fold higher in PDE7 overexpressing cells compared to the controls, whereas an <i>in vitro</i> specificity of up to 90% was measured. <i>Ex vivo</i> metabolite studies revealed a high fraction of intact parent in the rat brain (98% at 5 min and 75% at 30 min postinjection). Considerable brain penetration was further corroborated by <i>ex vivo</i> biodistribution and PET imaging studies, the latter showing heterogenic brain uptake. While marginal blockade was observed by PET studies in rodents, a moderate, but dose-dependent, blockade was observed in the non-human primate brain following pretreatment with nonradioactive <b>27</b>. Accordingly, [¹¹C]<b>27</b> will serve as a valuable lead compound for the development of a new arsenal of PDE7-targeted probes.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1835–1843"},"PeriodicalIF":4.0,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00385","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036374","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}

{"title":"Therapeutic Divergence in 5-HT2A Agonism: Psilocybin and Phenalkylamines for Demoralization Syndrome","authors":"Robert B. Kargbo*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00475","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00475","url":null,"abstract":"<p >Novel phenalkylamines and tryptamines such as psilocybin demonstrate promising nontraditional pharmacological profiles for treating psychiatric syndromes. Structural modifications yield functional selectivity at 5-HT receptors, mitigating hallucinogenic risk while preserving therapeutic efficacy. This study integrates receptor and behavioral data to support phenalkylamines and psilocybin as rational therapeutics for demoralization syndrome and depression-related conditions.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1719–1720"},"PeriodicalIF":4.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036695","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}

{"title":"Discovery of Novel Isofunctional SARS-CoV-2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual Screening","authors":"Cindy Meyer,&nbsp;Mayako Michino,&nbsp;David J. Huggins,&nbsp;Aitor Garzia,&nbsp;Jada A. Davis,&nbsp;Michael W. Miller,&nbsp;Nigel Liverton,&nbsp;Hans-Heinrich Hoffmann,&nbsp;J. Fraser Glickman,&nbsp;Julius Nitsche,&nbsp;Oleg Ganichkin,&nbsp;Stefan Steinbacher,&nbsp;Charles M. Rice,&nbsp;Peter T. Meinke and Thomas Tuschl*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00339","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00339","url":null,"abstract":"<p >In early 2020, SARS-CoV-2 spread into a worldwide pandemic, causing more than 7 million deaths. Direct-acting antivirals (DAAs) complementing vaccines and mitigating severe disease in at-risk populations remain important. Here, we used a structure-based virtual screening (SBVS) workflow to identify new SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14. We virtually screened the Enamine and Sigma in-stock screening collections as well as the 3 orders of magnitude larger Enamine REAL make-on-demand compound library, which produced better docking scores and higher virtual hit rates. While biochemical testing of 145 in-stock library compounds yielded a single NSP14-specific inhibitor, 123 chemically synthesized Enamine REAL SBVS compounds contained 10 hits specifically inhibiting NSP14 with half-maximal inhibitory concentrations (IC₅₀) below 10 μM. The new compounds were chemically distinct in atomic composition from any NSP14 inhibitors previously identified by conventional biochemical high-throughput screening (HTS) and may serve as starting points to develop novel SARS-CoV-2 DAAs.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1789–1797"},"PeriodicalIF":4.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00339","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036696","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}