Journal of Medicinal Chemistry最新文献

{"title":"Correction to “Discovery of Novel Arylethynyltriazole Ribonucleosides with Selective and Effective Antiviral and Antiproliferative Activity”","authors":"Jinqiao Wan, Yi Xia, Yang Liu, Menghua Wang, Palma Rocchi, Jianhua Yao, Fanqi Qu, Johan Neyts, Juan L. Iovanna, Ling Peng","doi":"10.1021/acs.jmedchem.5c02591","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02591","url":null,"abstract":"In Figure 7, tumor volumes were incorrectly calculated. The corrected Figure 7 is provided below in this Addition/Correction. This error does not affect the statistical significance of the results or the conclusions of the study. The authors regret this error. Figure 7. Effect of <b>3f</b> treatment on chemoresistant MiaPaCa-2 tumor growth in vivo. Nude mice bearing MiaPaCa-2 tumors of 100 mm³ were randomly selected for treatment with <b>3f</b> and no treatment as control. <b>3f</b> was injected intraperitoneally (150 (mg/kg)/mice) every 3 days for 4 weeks and tumor volume measured once a week. All of the results were expressed as the mean ± SE (<i>n</i> = 5): points, mean values of analysis; bars, standard errors; *, differing from control (<i>p</i> ≤ 0.05), **, differing from control (<i>p</i> ≤ 0.01) by Student’s <i>t</i> test. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127955","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":"Call for Papers: Macrocycles as Therapeutic Modalities for Challenging Drug Targets","authors":"Weibo Yang","doi":"10.1021/acs.jmedchem.5c02525","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02525","url":null,"abstract":"The perception of what constitutes a viable therapeutic agent has expanded considerably, moving beyond traditional small molecules to embrace more complex architectures. Among these, macrocyclic compounds have emerged as a promising class due to their unique ability to modulate challenging biological targets. Unlike conventional small molecules, macrocycles possess intermediate molecular weights, conformational restraint, and extended surface areas that enable high-affinity binding to flat protein surfaces and protein–protein interaction interfaces─targets often deemed “undruggable”. Notably, among human disease-related target proteins, up to 85% are still considered undruggable. (1) Macrocycles offer a compelling combination of adaptability, selectivity, and improved pharmacological profiles. (2) Their cyclic structures reduce conformational entropy upon binding, enhancing target engagement and increasing binding affinity. These characteristics make them particularly valuable for interfering with intricate biomolecular interactions that are central to disease mechanisms but remain elusive to typical small molecules or biologics (Figure 1). Recent years have witnessed significant advances in synthetic strategies, computational design, and biological evaluation of macrocyclic compounds. Hiroaki Suga, (3) Christian Heinis, (4) Herbert Waldmann, (5) Felix Hausch, (6) Jan Kihlberg, (7) Mate Erdelyi, (2) Ke Ding, (8) Honglin Li, (9) Xiaoyun Lu, (10) we (11) and others have contributed to advancing research on the medicinal chemistry of macrocycles. Notably, macrocycles have shown promise in targeting oncogenic proteins such as KRAS, transcription factors, and various regulatory complexes through innovative mechanisms, including molecular glue strategies that induce neomorphic interactions. Furthermore, the integration of macrocyclic scaffolds with peptide, (3,11) peptidomimetic, or synthetic chemistries has broadened the horizon for developing compounds with enhanced stability, membrane permeability, and oral bioavailability. Despite these advances, the development of macrocyclic therapeutics continues to face considerable challenges. Limitations in synthetic accessibility, structural diversification, and predictive modeling hinder the efficient exploration of chemical space. There is a pressing need for novel macrocyclization methodologies, efficient screening platforms, and strategies to optimize the drug-like properties of macrocyclic compounds. This Special Issue of the Journal of Medicinal Chemistry, dedicated to “Macrocycles as Therapeutic Modalities for Challenging Drug Targets”, invites contributions that highlight recent innovations in the design, synthesis, and application of macrocycles as therapeutic agents. Topics of interest include, but are not limited to Novel macrocyclization reactions and strategies Computational design and modeling of macrocyclic compounds Macrocyclic peptides and peptidomimetics Targeted protein degradation and mol","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116724","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":"p-Alkoxy-Substituted Anisomycins with Potent Anti-Trypanosomiasis Activity and Expanded Modes of Action","authors":"Kajumee Bora Bhowal, Anh Minh Thao Nguyen, Ana Victoria Ibarra-Meneses, Andressa Brito Lira, K. Shanmugha Rajan, Jesus D. Castaño, Francis Beaudry, Anat Bashan, Christopher Fernandez-Prada, Martin Olivier, Ada Yonath, William D. Lubell","doi":"10.1021/acs.jmedchem.5c01291","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01291","url":null,"abstract":"Neglected tropical diseases caused by trypanosomatid parasites present a major public healthcare issue, partly due to emerging resistance. Attachment of ω-alkynyl chains characteristic of the lipid tails of antiparasitic peptides to the <i>p</i>-position of anisomycin gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant <i>Leishmania</i> strains. Single-particle cryoelectron microscopy analysis revealed that <i>O</i>-propargyl anisomycin binds to the highly conserved peptidyl transferase center of the ribosome similar to the parent inhibitor. Thermal proteomic profiling and gene ontology analysis demonstrated that <i>O</i>-propargyl anisomycin exhibited a broader mode of action, including activity against glycosome-associated proteins. Alkynyl substituents improved antiparasitic activity against resistant strains, likely by enlarging the mode of action, offering a novel path toward therapy against trypanosomatid infections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103628","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 PF-07054894, a Potent Squaramide-Based CCR6 Antagonist Displaying High CXCR2 Selectivity.","authors":"Mark E Schnute,Huixian Wu,John I Trujillo,Wei Li,David Jonathan Wasilko,Jennifer Alley,Eric P Arnold,Scott W Bagley,Gabriel Berstein,David C Blakemore,Mark W Bundesmann,Gary M Chinigo,Chulho Choi,Robert Cooke,Kimberly Crouse,Alpay Dermenci,Theresa Dickinson,Andrew Flick,Richard K Frisbie,Carmen Garcia-Irizarry,Brian S Gerstenberger,David Hepworth,Neelu Kaila,Daniel W Kung,Daniel Lamb,Sophie Y Lavergne,David C Limburg,Shenping Liu,Vincent M Lombardo,Prolay K Mondal,James J Mousseau,Arjun Narayanan,Nootaree Niljianskul,Philippe Nuhant,Senliang Pan,Michael J Primiano,Mathieu Rappas,Daniel C Schmitt,Stefanus J Steyn,Ray Unwalla,Dipy Vasa,Michael L Vazquez,Fabien Vincent,Xiaojing Yang,Atli Thorarensen","doi":"10.1021/acs.jmedchem.5c01946","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01946","url":null,"abstract":"The G protein-coupled receptor (GPCR) CCR6 mediates the migration of pathogenic immune cells to the site of inflammation in response to the chemokine CCL20. CCR6 is an attractive target for the treatment of chronic autoimmune disease as antagonism of the receptor is expected to block CCL20-mediated immune cell recruitment. High-throughput-screening identified a squaramide-based, allosteric antagonist of CCR6 that potently inhibited CCL20-mediated T cell chemotaxis, but it also inhibited CXCL1-mediated neutrophil chemotaxis through CXCR2 antagonism. Lead optimization achieved differentiation from CXCR2 through identification of a methyl substituent-dependent selectivity switch or \"magic methyl for selectivity\". The mechanism for this effect is rooted in different antagonist-induced ligand-receptor behaviors, insurmountable for CCR6 and surmountable for CXCR2. Herein, we report the discovery and preclinical evaluation of the CCR6 antagonist PF-07054894 (18l) which has advanced to clinical trials as a first in class approach targeting the receptor.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103408","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":"Recent Advances in Peptide Linkers for Antibody-Drug Conjugates","authors":"Shaoting Li, Yu Guo, Jinxin Che, Haibin Dai, Xiaowu Dong","doi":"10.1021/acs.jmedchem.5c01982","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01982","url":null,"abstract":"Antibody-drug conjugates (ADCs) are at the forefront of next-generation targeted cancer therapies, owing to their high specificity and potent cytotoxicity. The linker within ADCs plays a critical role in balancing efficacy and safety. Cleavable peptide linkers, dominating clinical-stage ADC design due to their capacity for selective drug release, nonetheless face challenges such as structural homogeneity, limited mouse plasma stability, and insufficient hydrophobicity improvement. Consequently, developing novel peptide linkers with enhanced stability, selectivity, and physicochemical properties is a key research focus. Here, by highlighting the cleavable peptide linkers used in clinical-stage ADCs and summarizing novel strategies in next-generation linker designs, we provide a timely overview of advances in peptide linkers, covering new peptide or peptidomimetic sequences, exolinker strategies, dual-cascade triggering mechanisms, and hydrophilic modifications. This review aims to offer a theoretical foundation and research insights for innovative linker design, thereby advancing next-generation ADCs to meet the growing demand for precision therapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"85 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103629","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":"Translational Research on the Oral Delivery of the Cytotoxic PROTAC Molecule via Tumor-Targeting Prodrug Strategy for Triple-Negative Breast Cancer Treatment.","authors":"Huayu Hu,Yubo Wang,Mengmeng Wang,Zixuan Zhang,Xiaoting Gu,Ruixia Sun,Xinqiang Liu,Ning Li,Na Ding,Weiya Li,Xingli Zhao,Chao Li,Ziqi Huang,Xin Wang,Xiru Li,Shuangwei Liu,Shuang Yang,Guang Yang","doi":"10.1021/acs.jmedchem.5c01640","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01640","url":null,"abstract":"In the present work, we have identified a proteolysis targeting chimera (PROTAC) molecule that potently and selectively degrades CDK4, CDK6, and CDK9, inhibiting triple-negative breast cancer (TNBC) cell proliferation at low nanomolar concentrations. However, its low bioavailability and significant in vivo toxicity in experimental animals limit clinical translation. To address this challenge, we identified an oral bioavailable and tumor-targeting prodrug that substantially reduces systemic exposure of the PROTAC compound while enabling significant tumor-specific enrichment. This prodrug effectively and safely inhibits TNBC cell proliferation in multiple cell line-derived xenografts (CDX) and patient-derived xenograft (PDX) models, positioning it as a promising candidate for targeted TNBC therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"60 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103579","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":"Design, Synthesis, and Biological Evaluation of Arginine N-Glycosylation Stapled Peptides with Potent Antitumor Activity In Vivo.","authors":"Yinxue Fu,Chunhui Dou,Xiaoyang Gao,Shanping Ji,Xuemei Zhao,Jingwen Xue,Hao Yang,Nannan Song,Chunyu Zhang,Changlong Wang,Yulei Li","doi":"10.1021/acs.jmedchem.5c01550","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01550","url":null,"abstract":"The host defense peptide PP-1 has attracted attention for its strong antitumor activity. However, its potential for clinical use is hindered by its poor proteolytic stability. In this study, a series of stapled PP-1 derivatives were obtained by an all-hydrocarbon stapling strategy and arginine N-glycosylation, and five rounds of peptide libraries containing more than 60 stapled and/or arginine N-glycosylated peptides were rationally constructed. PP-60 exhibited superior in vitro antitumor activities and low hemolytic toxicity. Compared with the parent peptide PP-1, PP-60 exhibited improved proteolytic and serum stability and, importantly, significantly weakened hemolysis and potential toxicity to liver tissue. Confocal microscopy revealed the superior cell permeability of PP-60. Flow cytometry revealed that PP-60 could exert its antitumor effects by inducing apoptosis. Notably, PP-60 displayed a potent therapeutic effect without obvious side effects in a nude mouse model. PP-60 holds promise for further development as a lead antitumor agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"317 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103407","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 Fluoroalkenes as Dual Inhibitors of Diacylglycerol Kinases Alpha and Zeta (DGKα/ζ)","authors":"Ming Xiang, Shicheng Shi, Shaoqun Qian, Chengtsung Lai, Kelly Federowicz, Guofeng Zhang, Melissa Chan, David Rodrigues, Bihui Melidosian, Jeff Jackson, Gengjie Yang, Maryanne Covington, Lisa Truong, Michelle Frascella, Rodrigo Hess, Patrick Mayes, Xiaodi Ren, Sunkyu Kim, Joshua R. Hummel, Xiaozhao Wang","doi":"10.1021/acs.jmedchem.5c02098","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02098","url":null,"abstract":"Diacylglycerol kinases alpha and zeta (DGKα/ζ) are negative regulators of T cell receptor signaling that suppress immune system activation. As such, dual inhibition of DGKα and ζ represents a promising strategy to enhance antitumor immunity, making these kinases attractive targets for cancer immunotherapy. Herein, we report the discovery of a series of fluoroalkenes as potent dual inhibitors of DGKα and ζ. A high-throughput screening campaign identified amide <b>1</b> with micromolar activity against DGKζ. While SAR studies revealed amides with potent dual DGKα/ζ activity, replacing the amide with a fluoroalkene bioisostere led to a significant improvement in cellular activity. Systematic SAR studies led to the discovery of lead compound <b>17</b>, a potent dual DGKα/ζ inhibitor with balanced in vitro ADME properties and favorable pharmacokinetic profiles. The in vivo functional activity of compound <b>17</b> was demonstrated in an OT-1 pharmacodynamic murine model, showing robust and dose-dependent immune activation in the presence of antigen presentation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089642","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":"Optimization of Physicochemical Properties and ADME for 2,4-Substituted 1H-Pyrrolo[2,3b]pyridines Inhibitors of Trypanosome Proliferation","authors":"Kelly A. Bachovchin, Rosario Díaz, Gloria Ceballos-Perez, Domingo Rojas-Barros, Guiomar Pérez-Moreno, Raquel García-Hernández, Cristina Bosch-Navarrete, Mitch Rivers, Erica C. Penn, Norma E. Roncal, Richard J. Sciotti, Robert F. Campbell, Maria Santos Martinez-Martinez, Pilar Manzano-Chinchon, Luis Miguel Ruiz-Perez, Miguel Navarro, Dolores González-Pacanowska, Michael P. Pollastri, Lori Ferrins, Baljinder Singh","doi":"10.1021/acs.jmedchem.5c01217","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01217","url":null,"abstract":"Neglected tropical diseases, such as human African trypanosomiasis (HAT), require novel treatments that can populate the clinical pipeline in the event of rising resistance and treatment recrudescence. Following a high-throughput screen of almost 42,000 human kinase inhibitor chemotypes, we identified a 2,4-disubstituted azaindole that had good antiparasitic activity, selectivity, and predicted brain exposure, but that failed to meet our criteria for advancement into an efficacy study. Following hit-to-lead optimization, we arrived at <b>18a,</b> which offered the best combination of potency, properties, and pharmacokinetic parameters, and, while not curative, this work leads to opportunities for continued optimization for HAT and cutaneous leishmaniasis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089639","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 Novel 4,5-Dihydropyrrolo[3,4-c]pyrazol-6(2H)-one-Based Tubulin Inhibitors Targeting Colchicine Binding Site with Potent Anti-Ovarian Cancer Activity.","authors":"Quanwei Yu,Yujie Liu,Zhijia Wang,Chengyong Wu,Ruofei Zhang,Lun Tan,Lele Zhang,Cuiyu Guo,Lantu Gou,Weimin Li,Yang He,Yuxi Wang","doi":"10.1021/acs.jmedchem.5c00014","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00014","url":null,"abstract":"To address the toxicity of current microtubule inhibitors, we employed the GeminiMol deep learning model to screen the Zinc20 database, identifying a novel 4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one scaffold (Y1) targeting the colchicine binding site. Subsequent optimization culminated in Y60s, a potent antiproliferative agent (SKOV3 IC50 = 0.025 μM) that inhibits clonogenic formation, migration, and invasion of ovarian cancer cells. Y60s inhibited tubulin polymerization which in turn induced G2/M arrest and apoptosis in SKOV3 cells. Y60s demonstrated potent antitumor activity without observable toxicity in an SKOV3 xenograft model. The cocrystal structure of Y8 in complex with tubulin was resolved, confirming the key binding mode of 4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one compounds. This work showcases Y60s as a promising novel tubulin inhibitor and highlights the utility of deep learning model for rapid identification of bioactive compounds from large chemical databases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093572","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}