ACS Medicinal Chemistry Letters最新文献_第4页

Crystal Structure of the Sigma-2 Receptor Complexed with Investigational Drug Zervimesine (CT1812) Sigma-2受体与研究药物Zervimesine （CT1812）复合物的晶体结构

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ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-07 DOI: 10.1021/acsmedchemlett.6c00215

Gary C. Look, Dominic Gilzer, Franziska Preuss, Jan Wollenhaupt, Julius Nitsche, Jérôme Amaudrut, Savina Malancona, Christian A.G.N. Montalbetti, Anthony O. Caggiano, Mary E. Hamby

{"title":"Crystal Structure of the Sigma-2 Receptor Complexed with Investigational Drug Zervimesine (CT1812)","authors":"Gary C. Look, Dominic Gilzer, Franziska Preuss, Jan Wollenhaupt, Julius Nitsche, Jérôme Amaudrut, Savina Malancona, Christian A.G.N. Montalbetti, Anthony O. Caggiano, Mary E. Hamby","doi":"10.1021/acsmedchemlett.6c00215","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00215","url":null,"abstract":"The investigationaldrug zervimesine (CT1812) is an allostericsmall molecule modulator of the sigma-2 receptor (S2R), known as transmembraneprotein 97 (TMEM97), currently in clinical development for Alzheimer’sdisease and dementia with Lewy bodies. In Phase 2 trials, consistentfavorable trends across outcome measures were observed for Alzheimer’sdisease (NCT03507790), dementia with Lewy Bodies (NCT05225415), andanother indication, dry AMD (NCT05893537). The crystal structure ofS2R complexed with zervimesine to 2.74 Å resolution reveals thisinvestigational therapeutic bound in the binding site of S2R analogousto that seen previously with other S2R ligands, and is consistentwith binding affinity data from a S2R competition assay. The structuralinteractions by which zervimesine binds with S2R are illuminated,which may shed light on the potential structure–function relationshipunderlying the favorable effects of zervimesine seen preclinicallyand clinically, and may foster the design of future S2R modulatorsfor neurodegenerative conditions.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1925–1932"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915741","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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Discovery of Forvisirvat (DS-7830a/SP-624), a Brain-Penetrant Sirtuin 6 Activator Derived from Griseofulvin with Antidepressant-Like Effects Forvisirvat （DS-7830a/SP-624）是一种脑渗透Sirtuin 6激活剂，从灰黄霉素中提取，具有抗抑郁样作用

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-26 DOI: 10.1021/acsmedchemlett.6c00366

Yasuyuki Ogawa, Keiji Saito, Katsuyoshi Nakajima, Osamu Iwamoto, Kazumasa Aoki, Mitsuhiro Makino, Shinji Tanaka, Nobuya Kurikawa, Eriko Michishita-Kioi, Seiko Nagata, Yoko Fujita, Masato Sasaki, Akiko Kasahara, Isao Yasumatsu, Makoto Hirasawa, Wataru Saitoh

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Peak Fiction: XRPD and the Illusion of Novelty 巅峰小说：XRPD和新奇的幻觉

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ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-06 DOI: 10.1021/acsmedchemlett.6c00339

Jeremy Rolquin, Shahin Shams, Mike Faley

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Molecular Striptease of a Thiadiazolopyrimidine Hit Yields a Streamlined, Artifact-Free NADPH Mimic for NOX Inhibition 噻二唑嘧啶的分子剥离产生了一种流线型的、无伪影的NADPH模拟物，用于抑制NOX

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-08 DOI: 10.1021/acsmedchemlett.6c00370

Emanuele Fabbrizi, Andrea Mancini, Chiara Lambona, Salvatore Macrì, Marianna Nalli, Francesco Quilli, Federico Pandolfi, Domenico Raimondo, Sara Marchese, Andrea Mattevi, Jihyeon Lee, Minhye Choi, Yun Soo Bae, Nadya Hristova-Avakumova, Magdalena Kondeva-Burdina, Denitsa Stefanova, Neda Anastassova, Sergio Valente, Dante Rotili, Antonello Mai

{"title":"Molecular Striptease of a Thiadiazolopyrimidine Hit Yields a Streamlined, Artifact-Free NADPH Mimic for NOX Inhibition","authors":"Emanuele Fabbrizi, Andrea Mancini, Chiara Lambona, Salvatore Macrì, Marianna Nalli, Francesco Quilli, Federico Pandolfi, Domenico Raimondo, Sara Marchese, Andrea Mattevi, Jihyeon Lee, Minhye Choi, Yun Soo Bae, Nadya Hristova-Avakumova, Magdalena Kondeva-Burdina, Denitsa Stefanova, Neda Anastassova, Sergio Valente, Dante Rotili, Antonello Mai","doi":"10.1021/acsmedchemlett.6c00370","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00370","url":null,"abstract":"The convergence ofoxidative stress and inflammationdrives neurodegenerationand cancer, positioning NADPH oxidases (NOXs) as critical therapeutictargets. Starting from the polyfunctional thiadiazolopyrimidine hit 1, we systematically truncated its peripheral arms to mapminimum pharmacophoric requirements. While extensive clipping compromisedactivity, strategic optimization yielded the streamlined analogue 5. In silico, 5 acted as a competitive NADPHmimic; in cell-free assays, it maintained multi-isoform potency, inhibitingNOX1 and NOX5 at low-micromolar concentrations. In rat brain subcellularfractions, 1 and 5 demonstrated concentration-dependentneuroprotective and antioxidant efficacy (1–10 μM) bysuppressing lipid peroxidation and preserving mitochondrial and synaptosomalviability. Notably, chemical profiling proved that 5 successfullystripped away the pro-oxidant liabilities and radical-scavenging artifactsinherent to 1. In cancer, 1 displayed someantiproliferative activity, mainly in hematological malignancies.Compound 5, although aqueous solubility issues limitedits cellular antiproliferative performance, represents a specific,artifact-free architectural starting point for future selective NOXinhibitor development.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"2045–2054"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915763","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 9 本刊第17卷第9期

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ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 DOI: 10.1021/acsmedchemlett.6c00445

Chao Shen

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Improved Library of Pyrrolidine-2,3-dione Monomers as Antimicrobial and Antibiofilm Agents against Staphylococcus aureus 改进的吡咯烷-2,3-二酮单分子库作为金黄色葡萄球菌的抗菌和抗生物膜剂

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-07-30 DOI: 10.1021/acsmedchemlett.6c00283

Sanjay R. Kalliat, M. Alejandro Valdes-Pena, Joshua G. Pierce

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Discovery of Novel Small-Molecule Toll-like Receptor 2 Agonists via a Scaffold Hopping Strategy 通过支架跳跃策略发现新型小分子toll样受体2激动剂

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-20 DOI: 10.1021/acsmedchemlett.6c00351

Yueyue Zhu, Longhai Wang, Yuqi Chen, Yujie Wang, Zonglong Chen, Yingxia Li, Wei Zhang

{"title":"Discovery of Novel Small-Molecule Toll-like Receptor 2 Agonists via a Scaffold Hopping Strategy","authors":"Yueyue Zhu, Longhai Wang, Yuqi Chen, Yujie Wang, Zonglong Chen, Yingxia Li, Wei Zhang","doi":"10.1021/acsmedchemlett.6c00351","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00351","url":null,"abstract":"Toll-likereceptor 2 (TLR2) has emerged as a promisingtherapeutictarget for reversing tumor immunosuppression, and its agonists haveshown great potential for cancer immunotherapy. Herein, we reporta series of novel TLR2 agonists developed via scaffold hopping of SMU-Z1 and systematic structure–activity relationship(SAR) studies. Among these, C10 (EC50 = 0.035μM) was identified as the most promising compound, exhibitingpotent agonistic activity. Notably, C10 (HLM t1/2 > 60 min) achieves significantly improved metabolicstability, compared with SMU-Z1 (HLM t1/2 = 31.4 min). C10 is a selective TLR2/1agonist without activating TLR3, TLR4, TLR7 or TLR8. Moreover, C10 induced the secretion of pro-inflammatory cytokines, includingIL-1β, IL-6, and TNF-α, in human immune cells. Collectively,these data position C10 as a promising TLR2 agonist tofurther develop an immunotherapy candidate.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"2017–2026"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923746","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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Discovery and Structure–Activity Relationship Studies of Thienopyrroles as Group 2 Influenza A Entry Inhibitors 噻吩吡咯类2组甲型流感进入抑制剂的发现及构效关系研究

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-24 DOI: 10.1021/acsmedchemlett.6c00239

John P. Sloan, Ryan Bott, Carolina Q. Sacramento, Christian Zielinski, Destiny I. Durante, Norton P. Peet, Irina N. Gaisina, Lijun Rong, Terry W. Moore

{"title":"Discovery and Structure–Activity Relationship Studies of Thienopyrroles as Group 2 Influenza A Entry Inhibitors","authors":"John P. Sloan, Ryan Bott, Carolina Q. Sacramento, Christian Zielinski, Destiny I. Durante, Norton P. Peet, Irina N. Gaisina, Lijun Rong, Terry W. Moore","doi":"10.1021/acsmedchemlett.6c00239","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00239","url":null,"abstract":"The influenza A virushas been detrimental to public health forcenturies and continues to take the lives of tens of thousands ofpeople annually. Although current therapeutics have been effectivein the past, the emergence of drug-resistant strains underscores theneed for agents with new mechanisms of action. Here, we report thieno[3,2-b]pyrroles as novel group 2 influenza A virus entry inhibitors.In this study, we used a HA-based surrogate entry assay to performthe structure–activity relationship (SAR) studies to optimizethe lead compounds. Docking studies in the predicted hemagglutininbinding site provided insight into potential binding interactions.Mutagenesis studies supported the proposed binding site. We validatedthe lead compounds that were potent in pseudovirus against infectiousH3N2 strains including an oseltamivir-resistant strain. Lead compoundswere counter-screened against other pseudoviruses and found to beselective. Together, these findings establish thieno[3,2-b]pyrroles as a promising new scaffold for combating group 2 influenzaA viruses.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1966–1976"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923750","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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Adenosine 5′-Carboxamide-Based Inhibitors of METTL1 基于腺苷5 ' -羧胺的METTL1抑制剂

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-10 DOI: 10.1021/acsmedchemlett.6c00203

Olga Bobileva, Francesco Nai, Sandija Niedrite, Lidia Mayordomo Soler, Irena Leite, Amedeo Caflisch

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Accelerated Synthesis of Novel Indole-3-Sulfonamides Leveraging High-Throughput Experimentation 利用高通量实验加速合成新型吲哚-3-磺胺类药物

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-18 DOI: 10.1021/acsmedchemlett.6c00331

Olivia P. Bercher, Kaitlin Lupinacci, Michael J. Breslin, Abdellatif El Marrouni

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