{"title":"Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment","authors":"Yongzhi Chen, Kunyu Lu, Binhao Rong, Yuanmei Wen, Guanguan Li, Shuo Li, Deyin Guo, Qifan Zhou, Shuwen Liu, Xumu Zhang","doi":"10.1021/acs.jmedchem.4c01979","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01979","url":null,"abstract":"The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, <b>ATV2301</b> exhibited an excellent anti-influenza activity (EC<sub>50</sub>, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (<i>F</i> = 71.60%). The prodrug <b>ATV2301A</b> demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. <b>ATV2301</b> also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that <b>ATV2301</b>’s anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, <b>ATV2301</b> showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805054","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":"Move over COVID, Tuberculosis Is Once again the Leading Cause of Death from a Single Infectious Disease","authors":"Tomayo Berida, Craig W. Lindsley","doi":"10.1021/acs.jmedchem.4c02876","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02876","url":null,"abstract":"Figure 1. Antitubercular drugs in clinical use. (3,4) Table one was adapted from WHO’s 2023 Antibacterial agents in clinical and preclinical development. (16) NCR: No cross resistance, NCC: New chemical class; NT: New target; MoA: New mechanism of Action. Figure 2. Antitubercular agent in clinical development. Figure 3. Cell wall of mycobacteria (left), Gram-positive bacteria (center), and Gram-negative bacteria (right). The figure was adapted from “Plant Antibacterials: The Challenges and Opportunities”, Berida et al, <i>Heliyon</i> <b>2024</b>, 10 (10), e31145, with permission from Elsevier. (26) This article references 38 other publications. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797734","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}
Ke Li, Xing Hu, Xin-Yi Tu, Mao-Ying Xian, Lei-Lei Huang, Ting Huang, Rui Luo, Hui Jin, Zheng Liu
{"title":"Enhancing COVID-19 Vaccine Efficacy: Dual Adjuvant Strategies with TLR7/8 Agonists and Glycolipids","authors":"Ke Li, Xing Hu, Xin-Yi Tu, Mao-Ying Xian, Lei-Lei Huang, Ting Huang, Rui Luo, Hui Jin, Zheng Liu","doi":"10.1021/acs.jmedchem.4c01801","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01801","url":null,"abstract":"The controlled release of immunostimulatory agents represents a promising strategy to enhance vaccine efficacy while minimizing side effects. This study aimed to improve the efficacy of the RBD-Fc-based COVID-19 vaccine through combining of an iNKT cell agonist and a TLR7/8 agonist using covalent conjugation and temporal delivery. We hypothesized that these combinations would yield a more balanced Th1/Th2 immune response. For covalent conjugation, we employed an uncleavable linker and a self-immolative disulfide linker to conjugate α-galactosylceramide (αGC) to imidazoquinoline (IMDQ). The αGC-SS-IMDQ-Ac conjugate, designed with a prodrug strategy for controlled TLR7/8 agonist release, elicited a higher IFN-γ/IL-4 T cell response ratio than individual adjuvants or their admixture. In the temporal delivery approach, administering IMDQ followed by αGC after 2 h resulted in the highest IgG2a/IgG1 ratio, significantly surpassing other groups. A 6 h delay between glycolipid and IMDQ injections yielded balanced IgG responses, enhancing IgG, IgG1, and IgG2a levels synergistically.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"200 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793804","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":"Modulating Phosphorylation by Proximity-Inducing Modalities for Cancer Therapy","authors":"Qiuyue Zhang, Jia Yu, Qidong You, Lei Wang","doi":"10.1021/acs.jmedchem.4c02624","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02624","url":null,"abstract":"Abnormal phosphorylation of proteins can lead to various diseases, particularly cancer. Therefore, the development of small molecules for precise regulation of protein phosphorylation holds great potential for drug design. While the traditional kinase/phosphatase small-molecule modulators have shown some success, achieving precise phosphorylation regulation has proven to be challenging. The emergence of heterobifunctional molecules, such as phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase recruiting chimeras (PHORCs), with proximity-inducing modalities is expected to lead to a breakthrough by specifically recruiting kinase or phosphatase to the protein of interest. Herein, we summarize the drug targets with aberrant phosphorylation in cancer and underscore the potential of correcting phosphorylation in cancer therapy. Through reported cases of heterobifunctional molecules targeting phosphorylation regulation, we highlight the current design strategies and features of these molecules. We also provide a systematic elaboration of the link between aberrantly phosphorylated targets and cancer as well as the existing challenges and future research directions for developing heterobifunctional molecular drugs for phosphorylation regulation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"83 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793722","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}
Rebecca A. Gallego, Sujin Cho-Schultz, Matthew Del Bel, Anne-Marie Dechert-Schmitt, Joyann S. Donaldson, Mingying He, Mehran Jalaie, Rob Kania, Jean Matthews, Michele McTigue, Jamison B. Tuttle, Hud Risley, Dahui Zhou, Ru Zhou, Omar K. Ahmad, Louise Bernier, Simon Berritt, John Braganza, Zecheng Chen, Julie A. Cianfrogna, Michael Collins, Cinthia Costa Jones, Ciaran N. Cronin, Carl Davis, Klaus Dress, Martin Edwards, William Farrell, Scott P. France, Nicole Grable, Eric Johnson, Ted W. Johnson, Rhys Jones, Thomas Knauber, Jennifer Lafontaine, Richard P. Loach, Michael Maestre, Nichol Miller, Mark Moen, Sebastien Monfette, Peter Morse, Andrew Ross Nager, Mark Niosi, Paul Richardson, Allison K. Rohner, Neal W. Sach, Sergei Timofeevski, Joseph W. Tucker, Beth Vetelino, Lei Zhang, Sajiv K. Nair
{"title":"Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer","authors":"Rebecca A. Gallego, Sujin Cho-Schultz, Matthew Del Bel, Anne-Marie Dechert-Schmitt, Joyann S. Donaldson, Mingying He, Mehran Jalaie, Rob Kania, Jean Matthews, Michele McTigue, Jamison B. Tuttle, Hud Risley, Dahui Zhou, Ru Zhou, Omar K. Ahmad, Louise Bernier, Simon Berritt, John Braganza, Zecheng Chen, Julie A. Cianfrogna, Michael Collins, Cinthia Costa Jones, Ciaran N. Cronin, Carl Davis, Klaus Dress, Martin Edwards, William Farrell, Scott P. France, Nicole Grable, Eric Johnson, Ted W. Johnson, Rhys Jones, Thomas Knauber, Jennifer Lafontaine, Richard P. Loach, Michael Maestre, Nichol Miller, Mark Moen, Sebastien Monfette, Peter Morse, Andrew Ross Nager, Mark Niosi, Paul Richardson, Allison K. Rohner, Neal W. Sach, Sergei Timofeevski, Joseph W. Tucker, Beth Vetelino, Lei Zhang, Sajiv K. Nair","doi":"10.1021/acs.jmedchem.4c01930","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01930","url":null,"abstract":"Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (<b>21</b>, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"211 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793805","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":"Targeting HMGB1 and Its Interaction with Receptors: Challenges and Future Directions","authors":"Pingping Shen, Libang Zhang, Xuewa Jiang, Boyang Yu, Jian Zhang","doi":"10.1021/acs.jmedchem.4c01912","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01912","url":null,"abstract":"High mobility group box 1 (HMGB1) is a nonhistone chromatin protein predominantly located in the nucleus. However, under pathological conditions, HMGB1 can translocate from the nucleus to the cytoplasm and subsequently be released into the extracellular space through both active secretion and passive release mechanisms. The distinct cellular locations of HMGB1 facilitate its interaction with various endogenous and exogenous factors, allowing it to perform diverse functions across a range of diseases. This Perspective provides a comprehensive overview of the structure, release mechanisms, and multifaceted roles of HMGB1 in disease contexts. Furthermore, it introduces the development of both small molecule and macromolecule inhibitors targeting HMGB1 and its interaction with receptors. A detailed analysis of the predicted pockets is also presented, aiming to establish a foundation for the future design and development of HMGB1 inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793808","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":"Current Status and Perspectives of Novel Radiopharmaceuticals with Heterologous Dual-targeted Functions: 2013–2023","authors":"Zuojie Li, Qing Ruan, Yuhao Jiang, Qianna Wang, Guangxing Yin, Junhong Feng, Junbo Zhang","doi":"10.1021/acs.jmedchem.4c01608","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01608","url":null,"abstract":"Radiotracers provide molecular- and cellular-level information in a noninvasive manner and have become important tools for precision medicine. In particular, the successful clinical application of radioligand therapeutic (RLT) has further strengthened the role of nuclear medicine in clinical treatment. The complicated microenvironment of the lesion has rendered traditional single-targeted radiopharmaceuticals incapable of fully meeting the requirements. The design and development of dual-targeted and multitargeted radiopharmaceuticals have rapidly emerged. In recent years, significant progress has been made in the development of heterologous dual-targeted radiopharmaceuticals. This perspective aims to provide a comprehensive overview of the recent progress in these heterologous dual-targeted radiopharmaceuticals, with a special focus on the design of ligand structures, pharmacological properties, and preclinical and clinical evaluation. Furthermore, future directions are discussed from this perspective.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793806","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}
Mohammed Monsoor Shaik, Samuel Pasco, Alessio Romerio, Carlo Pifferi, Silvia Sesana, Francesca Re, Charl Xavier Bezuidenhout, Silvia Bracco, Alberto Fernandez-Tejada, Juan Anguita, Francesco Peri
{"title":"Development of a New Vaccine Adjuvant System Based on the Combination of the Synthetic TLR4 Agonist FP20 and a Synthetic QS-21 Variant","authors":"Mohammed Monsoor Shaik, Samuel Pasco, Alessio Romerio, Carlo Pifferi, Silvia Sesana, Francesca Re, Charl Xavier Bezuidenhout, Silvia Bracco, Alberto Fernandez-Tejada, Juan Anguita, Francesco Peri","doi":"10.1021/acs.jmedchem.4c02392","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02392","url":null,"abstract":"In this study, we formulated an alternative to AS01b by combining FP20, a synthetic TLR4 agonist, and QS21v, a minimal saponin adjuvant, aiming to improve the vaccine efficacy and stability. The phase transition temperature of FP20 was determined by using differential scanning calorimetry to be 43.9 °C, providing a foundation for the formulation process. The coformulation was prepared using a dry film method for even adjuvant distribution. Characterization by dynamic light scattering and nanoparticle tracking analysis revealed a uniform particle size distribution of ∼120 nm. Cryogenic electron microscopy (CryoEM) revealed nanosized interactions between FP20 and QS21v, forming stable structures that likely enhanced the antigen presentation and immune activation. These physicochemical properties contributed to a robust <i>in vivo</i> synergy, where the coformulation elicited significantly higher antigen-specific antibody titers compared to individual adjuvants. These findings suggest that the FP20+QS21v coformulation provides a potent, stable, and safer alternative to traditional adjuvants, enhancing both vaccine efficacy and immunogenicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789814","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":"Elaborate Structural Modifications Yielding Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Potent Neuraminidase Inhibitors with Significantly Improved Broad-Spectrum Antiresistance Profiles","authors":"Jiwei Zhang, Ruifang Jia, Huinan Jia, Ping Li, Yuanmin Jiang, Anna Bonomini, Chiara Bertagnin, Qiaojie Xu, Zhou Tan, Xiuli Ma, Arianna Loregian, Bing Huang, Xinyong Liu, Peng Zhan","doi":"10.1021/acs.jmedchem.4c02222","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02222","url":null,"abstract":"Inspired by our previous finding that targeting the 150-cavity with a multisite-binding strategy emerged as an effective approach to obtain more potent and selective neuraminidase (NA) inhibitors against influenza virus, we present here the design, synthesis, and optimization of novel boron-containing N-substituted oseltamivir (OSC) derivatives. Exploratory structure–activity relationship (SAR) studies led to the identification of compounds <b>27c</b> and <b>33c</b> as the most potent NA inhibitors, surpassing OSC in potency against both wild-type group-1 NAs and oseltamivir-resistant NAs. These compounds demonstrated significant antiviral activity against several wild-type strains and H1N1pdm09 strains (EC<sub>50</sub> = 0.03 ± 0.005 and 0.03 ± 0.0008 μM, respectively). Additionally, these compounds did not exhibit significant toxicity (CC<sub>50</sub> > 200 μM in CEF cells; CC<sub>50</sub> > 250 μM in MDCK cells). These findings highlight <b>27c</b> and <b>33c</b> as promising next-generation anti-influenza agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788447","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}
Pan Chen, Yu Zou, Xiemin Wang, Zhichao Chen, Ke Dong, Jun Yang, Yaqian Cui, Jing Gu, Xinyi Wu, Xiaobo Li, Ying Zhou, Mi Guo, Zhiwei Zheng, Qi Chen, Weiwei Zhu, Di Wu, Lina Yin, Lingfeng Chen, Qin Ouyang, Guang Liang, Qidong Tang
{"title":"Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties","authors":"Pan Chen, Yu Zou, Xiemin Wang, Zhichao Chen, Ke Dong, Jun Yang, Yaqian Cui, Jing Gu, Xinyi Wu, Xiaobo Li, Ying Zhou, Mi Guo, Zhiwei Zheng, Qi Chen, Weiwei Zhu, Di Wu, Lina Yin, Lingfeng Chen, Qin Ouyang, Guang Liang, Qidong Tang","doi":"10.1021/acs.jmedchem.4c02401","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02401","url":null,"abstract":"Myeloid differentiation primary response 88 (MyD88) plays a central role in inflammatory responses and diseases. However, only a few inhibitors of MyD88 with some limits have been reported currently. Herein, we identified a lead compound (<b>L7</b>) through virtual screening and synthesized twenty-seven <b>L7</b> derivatives. An optimal compound (<b>A5</b>) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2<i>H</i>-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer <b>A5S</b> showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. <b>A5S</b> had good stability and safety, showed the highest distribution concentration in the lungs, and exhibited good therapeutic effects on LPS-induced and sepsis-induced ALI mouse models. Most importantly, <b>A5S</b> showed advantages in PK properties, and was identified as a promising MyD88 inhibitor with favorable drug-like properties, compared to the only approved MyD88 inhibitor, <b>TJ-M2010-5</b>, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors <b>LM8</b>.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"82 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788481","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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