ACS Medicinal Chemistry Letters最新文献

{"title":"In This Issue, Volume 15, Issue 10","authors":"Simone V. Bigi-Botterill*, ","doi":"10.1021/acsmedchemlett.4c0045310.1021/acsmedchemlett.4c00453","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00453https://doi.org/10.1021/acsmedchemlett.4c00453","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407633","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":"Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders","authors":"Rui Yang,&nbsp;Betsy Pray,&nbsp;Lapo Alinari*,&nbsp;Pui Kai Li* and Xiaolin Cheng*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0025510.1021/acsmedchemlett.4c00255","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00255https://doi.org/10.1021/acsmedchemlett.4c00255","url":null,"abstract":"<p >Transducin β-like protein 1 X-linked (TBL1X) is an essential scaffold protein involved in multiple signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Recent studies, however, suggest that TBL1X might modulate Wnt-regulated genes independently of β-catenin in diffuse large B-cell lymphoma (DLBCL). Here, we developed selective TBL1X degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy as a proof-of-concept. Eight PROTACs showed strong cytotoxic activity. Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation. Our mechanistic study revealed that TBL1X degradation induced by <b>TD11</b> relied on the formation of the ternary complex and was dependent on the proteasome. The TBL1X degraders developed in this study could be a valuable chemical tool for investigating TBL1X-related pathways.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402709","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":"Lasamide, a Potent Human Carbonic Anhydrase Inhibitor from the Market: Inhibition Profiling and Crystallographic Studies","authors":"Chiara Baroni,&nbsp;Ilaria D’Agostino,&nbsp;Gioele Renzi,&nbsp;Jaydeo T. Kilbile,&nbsp;Yasinalli Tamboli,&nbsp;Marta Ferraroni*,&nbsp;Simone Carradori,&nbsp;Clemente Capasso,&nbsp;Fabrizio Carta* and Claudiu T. Supuran,&nbsp;","doi":"10.1021/acsmedchemlett.4c0034110.1021/acsmedchemlett.4c00341","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00341https://doi.org/10.1021/acsmedchemlett.4c00341","url":null,"abstract":"<p >Lasamide is a synthetic precursor and a contaminant of the diuretic Furosemide manufacturing process and represents a highly valuable building block for fragment-based drug discovery approaches. We assessed the ability of Lasamide to inhibit in vitro the human-expressed Carbonic Anhydrases by means of the stopped-flow technique, and we assessed its binding modes within hCAs II and XII-mimic catalytic clefts by X-ray crystallography. Interestingly, an unprecedented crystal form for the hCA IX mimic H-tag is reported and discussed herein.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404097","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":"Exploring the 1-(4-Nitrophenyl)-3-arylprop-2-en-1-one Scaffold for the Selective Inhibition of Monoamine Oxidase B","authors":"Rita Meleddu,&nbsp;Antonella Fais*,&nbsp;Benedetta Era,&nbsp;Sonia Floris,&nbsp;Simona Distinto,&nbsp;Antonio Lupia,&nbsp;Filippo Cottiglia,&nbsp;Alessia Onali,&nbsp;Erica Sanna,&nbsp;Daniela Secci,&nbsp;Giulia Atzeni,&nbsp;Laura Demuru,&nbsp;Pierluigi Caboni,&nbsp;Donatella Valenti and Elias Maccioni*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0024610.1021/acsmedchemlett.4c00246","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00246https://doi.org/10.1021/acsmedchemlett.4c00246","url":null,"abstract":"<p >A small library of 1-(4-nitrophenyl)-3-arylprop-2-en-1-one derivatives was synthesized to identify new human monoamine oxidase B selective inhibitors. Their inhibitory activity toward MAO-A and MAO-B isoforms was evaluated to determine their potency and selectivity. All newly synthesized compounds were nanomolar inhibitors of the B isoform with IC₅₀ concentrations ranging from 120 to 2.2 nM. Conversely, their activity toward the A isozyme was only observed at micromolar concentrations. Our results bear out the hypothesis that the 1,3-diarylpropenone scaffold could represent a valuable starting point for designing efficient and selective MAO-B inhibitors.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142403726","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":"Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand","authors":"Umed Singh,&nbsp;Girija Pawge,&nbsp;Sarita Rani,&nbsp;Chia-Hung Christine Hsiao,&nbsp;David F. Wiemer and Andrew J. Wiemer*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0037110.1021/acsmedchemlett.4c00371","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00371https://doi.org/10.1021/acsmedchemlett.4c00371","url":null,"abstract":"<p >While ester-based phosphonate prodrugs excel at delivering payloads into cells, their instability in plasma is a hurdle for their advancement. Here, we synthesized new aryl/acyloxy prodrugs of a phosphonate BTN3A1 ligand. We evaluated their phosphoantigen potency by flow cytometry and ELISA and their plasma and cellular metabolism by LC-MS. These compounds displayed low nanomolar to high picomolar potency. Addition of a <i>p</i>-isopropyl group to the phenyl substituent and use of cyclohexyl or <i>p</i>-methoxybenzyl groups as the acyloxy substituent significantly increased human, but not mouse or rat, plasma stability without negatively impacting potency. Combinations of these prodrug moieties further improved stability, with the best combination achieving a half-life of over 12 h in human plasma, a marked improvement on prior compounds. In contrast, oxane analogs improved water solubility and cellular payload delivery but remained unstable in human plasma. The studies suggest that certain ester-based phosphonate prodrugs quickly deliver active payloads inside cells and show substantial stability in human plasma.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142408247","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":"Design, Biological Characterization, and Discovery of Novel Cyclohexenyl Derivatives as Kinesin KIF18A Inhibitors for the Treatment of Ovarian Cancer","authors":"Chen Zhang, Peng Tu, Xiangyu Jia, Yuanfeng Xia, Biao Lu, Fanglong Yang, Siqin Wang, Lei Jin","doi":"10.1021/acsmedchemlett.4c00383","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00383","url":null,"abstract":"A novel class of kinesin KIF18A inhibitors were discovered through modification of the clinical compound AMG650. Structure–activity relationship (SAR) study led to the discovery of compound <b>16</b> with an alkenyl motif, a highly potent KIF18A inhibitor, which displayed a favorable pharmacological profile and excellent efficacy in a mouse model of an OVCAR-3 xenograft tumor. Oral administration of <b>16</b> can induce a dose-dependent antitumor efficacy in the OVCAR-3 model without significant reduction in body weight. Compound <b>16</b> showed potential as a candidate for the clinical treatment of ovarian cancer.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263870","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":"Call for Papers: Academic and Industrial Collaborations in Drug Discovery","authors":"Danielle Schultz, Eric Voight, Stevan W. Djuric","doi":"10.1021/acsmedchemlett.4c00435","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00435","url":null,"abstract":"Dear Colleagues, Given the considerable interest generated from our Virtual Special Issues on the topic of enabling chemistry technologies in drug discovery, (1,2) the Editorial Board at <i>ACS Medicinal Chemistry Letters</i> has decided to broaden this approach to include the positive impact of academic and industrial collaborations on the drug discovery process. The suggestions listed below for topics that can be covered represent only the tip of the iceberg. The subject matter may include development of new synthetic methodology/total synthesis in terms of applications to medicinal chemistry and chemical biology, as well as potential challenges at the intersection of total synthesis, biology, and medicine; the development of new synthetic methodology to produce better routes to drug candidates; or building blocks for parallel synthesis work or novel fragments for fragment-based drug discovery purposes. This could include photoredox chemistry or catalyst development, high-throughput experimentation-enabled reaction optimization, or chemistry techniques for DNA-encoded library production and screening. We will also include efforts in chemical proteomics, whether it be targeting identification proteomics or off-target profiling; research to identify and validate new targets using chemical probes, including novel photoaffinity probes; and novel and improved analytical methods (e.g., reduction of analysis time, impact of novel MS-based methods). We are open to other hot topic areas such as antibody–drug candidates, targeted protein degradation/molecular glues, small-molecule RNA regulation, and therapeutic area initiatives such as the prevention and treatment of tropical diseases. This research may be done, for example, through sponsored research collaborations or, alternatively, student internships. We look forward to receiving your submissions! Sincerely, The Editorial Team at <i>ACS Medicinal Chemistry Letters</i> <i>ACS Medicinal Chemistry Letters</i> encourages submissions of Letters, Notes, Technical Notes, Microperspectives, and Viewpoints highlighting the importance of academic and industrial collaborations. Submit your manuscript via ACS Paragon Plus and select “Academic and Industrial Collaborations in Drug Discovery” from the Special Issue dropdown box. Submissions will undergo the normal peer-review process and, and if accepted, will be published on a rolling basis. Once the Virtual Special Issue is complete, all articles will be publicized as a virtual collection, which will provide additional exposure for the work. The submission deadline is May 31, 2025. Please consider the Author Guidelines before submitting a manuscript. We welcome presubmission inquiries, which can be sent to eic@medchemlett.acs.org This article references 2 other publications. This article has not yet been cited by other publications.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263871","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":"Call for Papers: Academic and Industrial Collaborations in Drug Discovery","authors":"Danielle Schultz,&nbsp;Eric Voight and Stevan W. Djuric*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0043510.1021/acsmedchemlett.4c00435","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00435https://doi.org/10.1021/acsmedchemlett.4c00435","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402966","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":"Design, Biological Characterization, and Discovery of Novel Cyclohexenyl Derivatives as Kinesin KIF18A Inhibitors for the Treatment of Ovarian Cancer","authors":"Chen Zhang,&nbsp;Peng Tu,&nbsp;Xiangyu Jia,&nbsp;Yuanfeng Xia,&nbsp;Biao Lu*,&nbsp;Fanglong Yang,&nbsp;Siqin Wang and Lei Jin,&nbsp;","doi":"10.1021/acsmedchemlett.4c0038310.1021/acsmedchemlett.4c00383","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00383https://doi.org/10.1021/acsmedchemlett.4c00383","url":null,"abstract":"<p >A novel class of kinesin KIF18A inhibitors were discovered through modification of the clinical compound AMG650. Structure–activity relationship (SAR) study led to the discovery of compound <b>16</b> with an alkenyl motif, a highly potent KIF18A inhibitor, which displayed a favorable pharmacological profile and excellent efficacy in a mouse model of an OVCAR-3 xenograft tumor. Oral administration of <b>16</b> can induce a dose-dependent antitumor efficacy in the OVCAR-3 model without significant reduction in body weight. Compound <b>16</b> showed potential as a candidate for the clinical treatment of ovarian cancer.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402964","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":"Cyclic Glycopeptide Analogs of Endomorphin-1 Provide Highly Effective Antinociception in Male and Female Mice","authors":"James E. Zadina, Lajos Z. Szabo, Fahad Al-Obeidi, Xing Zhang, Leticia Ferreira Nakatani, Chidiebere Ogbu, M. Leandro Heien, Torsten Falk, Mitchell J. Bartlett, Robin Polt","doi":"10.1021/acsmedchemlett.4c00315","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00315","url":null,"abstract":"Opioids acting at the mu opioid receptor (MOR) remain the most effective treatment for moderate to severe pain, but their use is limited by serious side effects. We have shown that a cyclized analog of endomorphin-1 provided pain relief comparable to that of morphine with reduction or absence of several side effects, including abuse liability. Glycosylation can promote penetration of cellular barriers. Here we developed cyclic glycopeptide endomorphin (glycoEM) analogs as drug candidates for potent and long-lasting analgesia. The analogs were assessed in receptor binding and functional assays and for blood–brain barrier penetration by microdialysis and MS. Two of the analogs showed MOR selectivity and more potent and longer lasting antinociception than morphine in male and female mice. Comparable antinociception occurred at A2 doses 5-fold lower (20-fold on a molar basis) than morphine doses. The results support further study of the glycoEMs for clinical application.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263869","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}