Longbin Liu*, Peter D. Johnson, Matthew R. Mills, Penelope A. Turner, Michael E. Prime, Christopher J. Brown, Adrian Kotey, Samuel Coe, Paul R. Giles, Catherine Lloyd, Sarah Hayes, Frederic J. Marlin, Filippo Rota, Frank Herrmann, Manuela Heßmann, Sabine Schaertl, Franziska Zajicek, Stef De Lombaerde, Filipe Elvas, Jeroen Verhaeghe, Steven Staelens, Daniele Bertoglio, Xuemei Chen, Michael P. Conlon, Randall Davis, Samantha F. Ensor, James Haber, Kathryn C. Haber, Ming Min Hsai, John E. Mangette, William F. Penniman, Luca Anzillotti, Simone Esposito, Angelo Lembo, Laura Orsatti, Davide Ventre, Maria Veneziano, Christine Sandiego, Scott Haller, Gwendolyn A. Marriner, Ignacio Munoz-Sanjuan, Vinod Khetarpal, Jonathan A. Bard and Celia Dominguez,
{"title":"","authors":"Longbin Liu*, Peter D. Johnson, Matthew R. Mills, Penelope A. Turner, Michael E. Prime, Christopher J. Brown, Adrian Kotey, Samuel Coe, Paul R. Giles, Catherine Lloyd, Sarah Hayes, Frederic J. Marlin, Filippo Rota, Frank Herrmann, Manuela Heßmann, Sabine Schaertl, Franziska Zajicek, Stef De Lombaerde, Filipe Elvas, Jeroen Verhaeghe, Steven Staelens, Daniele Bertoglio, Xuemei Chen, Michael P. Conlon, Randall Davis, Samantha F. Ensor, James Haber, Kathryn C. Haber, Ming Min Hsai, John E. Mangette, William F. Penniman, Luca Anzillotti, Simone Esposito, Angelo Lembo, Laura Orsatti, Davide Ventre, Maria Veneziano, Christine Sandiego, Scott Haller, Gwendolyn A. Marriner, Ignacio Munoz-Sanjuan, Vinod Khetarpal, Jonathan A. Bard and Celia Dominguez, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 14","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5c01005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chirality-Guided Optimization of A<sub>2A</sub> Adenosine Receptor Antagonists for Enhanced Metabolic Stability and Antitumor Efficacy.","authors":"Wen Ding, Shuhao Liu, Wenjiang Liu, Zhijing Zhang, Jingyu Zhao, Xiaolei Zhang, Taoda Shi, Wenhao Hu","doi":"10.1021/acs.jmedchem.5c01141","DOIUrl":"10.1021/acs.jmedchem.5c01141","url":null,"abstract":"<p><p>Blockade of the A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR) by small-molecule antagonists holds promise for enhancing the efficacy of immune checkpoint inhibitors such as PD-L1 antibodies. However, many A<sub>2A</sub>AR antagonists suffer from limited clinical success due to poor metabolic stability. In this study, we introduce chirality into the A<sub>2A</sub>AR antagonist scaffold to address this challenge. This approach led to the discovery of (<i>S</i>)-<b>E8</b>, a chiral compound with markedly improved binding affinity, cellular activity, and <i>in vivo</i> potency compared with AZD4635, a Phase II clinical candidate. In contrast, its enantiomer (<i>R</i>)-<b>E8</b> displays rapid metabolism and low efficacy, highlighting the importance of stereochemistry for therapeutic performance. Mechanistic studies identified CYP1A2 as the primary enzyme driving the metabolic differences among the enantiomers. These findings underscore the value of chirality-guided design in optimizing drug-like properties and reveal CYP1A2's pivotal role in enantioselective metabolism, offering a promising direction for the development of next-generation A<sub>2A</sub>AR antagonists.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"14962-14980"},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zulma Santisteban Valencia, Jennifer Kingston, Filip Miljković, Hannah Rowbottom, Nadia Mann, Sophie Davies, Martin Ekblad, Silvio Di Castro, Karolina Kwapień, Erik Malmerberg, Stig D Friis, Thomas Lundbäck, Tomas Leek, Johan Wernevik
{"title":"Correction to \"Closing the Design-Make-Test-Analyze Loop: Interplay between Experiments and Predictions Drives PROTACs Bioavailability\".","authors":"Zulma Santisteban Valencia, Jennifer Kingston, Filip Miljković, Hannah Rowbottom, Nadia Mann, Sophie Davies, Martin Ekblad, Silvio Di Castro, Karolina Kwapień, Erik Malmerberg, Stig D Friis, Thomas Lundbäck, Tomas Leek, Johan Wernevik","doi":"10.1021/acs.jmedchem.5c01870","DOIUrl":"10.1021/acs.jmedchem.5c01870","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"15232"},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Wang,Zhaohu Deng,Xiaocun Li,Xiaomin Zhang,Xuejing Fan,Yong Wang
{"title":"Diversity-Oriented Synthesis toward the Discovery of Ferrocenophane-Appended GPX4 Inhibitors as Potent Ferroptosis Inducers with Drug Likeness.","authors":"Jing Wang,Zhaohu Deng,Xiaocun Li,Xiaomin Zhang,Xuejing Fan,Yong Wang","doi":"10.1021/acs.jmedchem.5c00839","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00839","url":null,"abstract":"Novel drug-like ferroptosis inducers with distinct chemotypes and enhanced potency are needed to overcome cancer therapy resistance. In this study, we reported a new series of ferrocenophane-appended GPX4 inhibitors as highly effective ferroptosis-inducing anticancer agents by leveraging the \"one-stone-kills-two-birds\" strategy. Through diversity-oriented synthesis and structure-activity relationship investigations, the [3]-ferrocenophane derivative ML210-ansaFc emerged as a standout candidate, demonstrating remarkable cytotoxicity and superior ferroptosis selectivity in cancer cells versus ML210. Mechanistic studies revealed, for the first time, the ROS-generating capability of bridged ferrocenes at the molecular and cellular levels, underscoring the dual functionality of ansa-ferrocenes in driving ferroptosis. ML210-ansaFc exhibited robust tumor growth suppression in 3D spheroid models, coupled with favorable drug-like properties, highlighting its potential as a therapeutic agent for intractable cancers. This work could pave the way for the development of metallocene-based chemotypes with diverse spatial configurations for the treatment of multiple diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"110 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryotaro Okawa,Irina Artsimovitch,Akira Katsuyama,Toyotaka Sato,Courtney C Aldrich,Satoshi Ichikawa
{"title":"Structure-Activity Relationship of Pseudouridimycin Focusing on the Improvement of Chemical Stability.","authors":"Ryotaro Okawa,Irina Artsimovitch,Akira Katsuyama,Toyotaka Sato,Courtney C Aldrich,Satoshi Ichikawa","doi":"10.1021/acs.jmedchem.5c00052","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00052","url":null,"abstract":"In recent years, the spread of drug-resistant bacterial infections has driven a critical demand for new antimicrobial agents with novel mechanisms of action. Pseudouridimycin (PUM) is a nucleoside antibiotic that inhibits bacterial DNA-dependent RNA polymerase (RNAP) by binding in the conserved active site that is distinct from the mutable allosteric sites targeted by the clinically approved rifamycin-class of antibiotics. However, translational development of PUM is compromised by its poor intrinsic chemical stability and competitive modality of inhibition with respect to UTP, which will require further augmentation of binding affinity. We have conducted structure-activity relationship (SAR) studies on PUM by approaching these two problems through the rational design of analogs based on the known PUM·RNAP X-ray cocrystal structure and through elucidation of the decomposition mechanisms.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin R Taft,Matthew J Hesse,Mulugeta Mamo,Dirksen E Bussiere,Richard Huang,Patrick S Lee,Laura Wedel,Ellena Growcott,Karen C Wolff,Kelli Kuhen,Johanna Abend,Kelly A Wong,Don Ganem,Vincent H J Leonard,David C Tully
{"title":"Discovery and Optimization of a Novel Series of Influenza A Virus Replication Inhibitors Targeting the Nucleoprotein Protein-Protein Interaction.","authors":"Benjamin R Taft,Matthew J Hesse,Mulugeta Mamo,Dirksen E Bussiere,Richard Huang,Patrick S Lee,Laura Wedel,Ellena Growcott,Karen C Wolff,Kelli Kuhen,Johanna Abend,Kelly A Wong,Don Ganem,Vincent H J Leonard,David C Tully","doi":"10.1021/acs.jmedchem.5c01233","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01233","url":null,"abstract":"Influenza A virus (IAV) is a negative-sense, single-stranded RNA virus that causes seasonal epidemic respiratory infections, with novel subtypes of IAV historically able to lead to pandemics that spread on a global scale. We conducted a phenotypic high-throughput screen (HTS) that identified compound 1 as a singleton hit. Resistant viral mutants generated against analog 2 revealed mutations in the nucleoprotein (NP). An X-ray cocrystal structure of NP in complex with compound 3 helped define the novel mechanism of action as disruption of the NP-NP protein-protein interaction (PPI), leading to inhibition of NP oligomerization and blocking viral replication. Medicinal chemistry optimization efforts resulted in the identification of compound 20 (VNT-101) as a potent IAV inhibitor with low nM activity across multiple subtypes. Compound 20 has attractive DMPK and physicochemical properties, and demonstrated robust antiviral activity in rodent models of influenza infection, leading to successful completion of IND-enabling safety studies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"59 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovery of Fulzerasib (GFH925) for the Treatment of KRAS G12C-Mutated Solid Tumors.","authors":"Tao Jiang,Chonglan Lin,Siyuan Le,Leitao Zhang,Tao Liang,Lijian Cai,Xiaoling Lan,Mei Ge,Zhubo Liu,Wan He,Ling Peng,Yanhui Zhao,Jinmin Ren,Feng Yan,Qiang Lu,Jiong Lan,Fusheng Zhou","doi":"10.1021/acs.jmedchem.4c03183","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03183","url":null,"abstract":"RAS mutations are the most prevalent genetic alterations in human tumors, accounting for 30% of all cases. Among these mutations, KRAS G12C emerged as the first druggable target through covalent attachment, which locks the protein in its inactive state. Employing a structure-based drug design strategy, we identified fulzerasib (GFH925), which features a novel lactam-based tetracyclic naphthyridinone scaffold. This molecule demonstrates high in vitro potency and selectivity, favorable pharmacokinetic profiles across species, and significant in vivo antitumor efficacy in various cancer-related xenograft models, including intracranial tumors. Fulzerasib has recently received accelerated approval in China for adult NSCLC patients with the KRAS G12C mutation after prior systemic therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"115 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovery of a Novel MNK Inhibitor (NSP-1047) with In Vivo Anti-acute Myeloid Leukemia Activity.","authors":"Bing Li,Shuang Xia,Ke Zhang,Qionglin Huang,Qin Chen,Jingwen Wang,Dizhou Wu,Jie Zhang,Yike Zou,Jianming Zhang","doi":"10.1021/acs.jmedchem.5c00504","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00504","url":null,"abstract":"MAPK-interacting kinases (MNKs) phosphorylate the eukaryotic initiation factor 4E (eIF4E), critical for cap-dependent translation. The MNK/eIF4E pathway plays a role in the development and progression of various hematological and solid tumors. Here, we report the discovery of a novel polycyclic compound 21e (NSP-1047), which inhibits MNK1 and MNK2 with high potency, leading to a reduction in the phosphorylation of eIF4E. NSP-1047 shows strong in vitro antiproliferative activity against multiple acute myeloid leukemia (AML) cell lines. Meanwhile, it enhances anticancer immune responses by downregulating the expression of immune checkpoint proteins and suppressing the secretion of inflammatory cytokines. NSP-1047 displays excellent ADME and pharmacokinetic properties, and encouraging safety profiles, with a highest nonsevere toxic dose (HNSTD) of 750 and 200 mg/kg for SD rats and Beagle dogs, respectively. In vivo efficacy evaluation in AML xenografts demonstrates significant tumor suppression, with tumor regression observed at tolerated doses, both as monotherapy and in combination with Ara-C or venetoclax.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure-Based Discovery of Hsp90/HDAC6 Dual Inhibitors Targeting Aggressive Prostate Cancer.","authors":"Andrea Citarella,Silvia Belluti,Davide Bonanni,Davide Moi,Isabella Piccinini,Arianna Rinaldi,Chiara Papulino,Rosaria Benedetti,Laura Cuoghi,Stefano Di Ciolo,Alessandra Silvani,Lucia Altucci,Luca Pinzi,Silvia Franchini,Daniele Passarella,Claudia Sorbi,Clelia Giannini,Carol Imbriano,Giulio Rastelli","doi":"10.1021/acs.jmedchem.5c00717","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00717","url":null,"abstract":"HDAC6 and Heat Shock Protein 90 (Hsp90) are key regulators within the androgen response pathway, exhibiting a close interplay and mutual interaction patterns that make their combined inhibition a promising strategy for treating aggressive prostate cancer (PC). Herein, we present the structure-based design of dual inhibitors of Hsp90 and HDAC6 that leveraged the crystal structure requirements of HDAC6 and two distinct Hsp90 binding pockets. The study led to the discovery of compound 17, a potent, nearly balanced, and selective dual inhibitor of HDAC6 and Hsp90 endowed with favorable drug-like properties. The compound demonstrated excellent antiproliferative activity across PC cell lines. In 3D tumor spheroid models, it demonstrated marked anticancer activity and ability to target both established tumor masses and tumor-initiating cell populations. Furthermore, combination studies showed marked synergistic effects that outperformed the coadministration of single-target inhibitors. Overall, compound 17 stands as a promising candidate for further preclinical evaluation against aggressive forms of PC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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