Journal of Medicinal Chemistry最新文献

{"title":"Small-Molecule Modulators Targeting Coactivator-Associated Arginine Methyltransferase 1 (CARM1) as Therapeutic Agents for Cancer Treatment: Current Medicinal Chemistry Insights and Emerging Opportunities.","authors":"Shuqing Li, Wanyi Pan, Chengpeng Tao, Zhihao Hu, Binbin Cheng, Jianjun Chen, Xiaopeng Peng","doi":"10.1021/acs.jmedchem.4c02106","DOIUrl":"10.1021/acs.jmedchem.4c02106","url":null,"abstract":"<p><p>Overexpression of coactivator associated arginine methyltransferase 1 (CARM1) is associated with various diseases including cancer. Therefore, CARM1 has emerged as an attractive therapeutic target and a drug response biomarker for anticancer drug discovery. However, the development of conventional CARM1 inhibitors has been hampered by their limited clinical efficacy, acquired resistance, and inability to inhibit nonenzymatic functions of CARM1. To overcome these challenges, new strategies such as isoform-selective inhibitors, dual-acting inhibitors, targeted protein degradation technology (e.g., PROTACs), and even activators, are essential to enhance the anticancer activity of CARM1 modulators. In this perspective, we first summarize the structure and biofunctions of CARM1 and its association with cancer. Next, we focus on the recent advances in CARM1 modulators, including isoform-selective CARM1 inhibitors, dual-target inhibitors, PROTAC degraders, and activators, from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and clinical status. Finally, we discuss the challenges and future directions for CARM1-based drug discovery.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589502","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":"Development of N-(4-(1H-Imidazol-1-yl)phenyl)-4-chlorobenzenesulfonamide, a Novel Potent Inhibitor of β-Catenin with Enhanced Antitumor Activity and Metabolic Stability","authors":"Michela Puxeddu, Lele Ling, Silvia Ripa, Michele D’Ambrosio, Marianna Nalli, Anastasia Parisi, Pietro Sciò, Antonio Coluccia, Arianna Granese, Martina Santelli, Domiziana Masci, Petra Cuřínová, Chiara Naro, Claudio Sette, Arianna Pastore, Mariano Stornaiuolo, Chiara Bigogno, Giulio Dondio, Laura Di Magno, Gianluca Canettieri, Te Liu, Romano Silvestri, Giuseppe La Regina","doi":"10.1021/acs.jmedchem.4c01708","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01708","url":null,"abstract":"The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the β-catenin armadillo repeat domain was not exhaustively explored. In order to get more insight, we synthesized novel <i>N</i>-(heterocyclylphenyl)benzenesulfonamides <b>6</b>–<b>28</b>. The new compounds significantly inhibited Wnt-dependent transcription as well as SW480 and HCT116 cancer cell proliferation. Compound <b>25</b> showed binding mode consistent with this hotspot binding region. Compound <b>25</b> inhibited the growth of SW480 and HCT116 cancer cells with IC₅₀’s of 2 and 0.12 μM, respectively, and was superior to the reference compounds <b>5</b> and <b>5-FU</b>. <b>25</b> inhibited the growth of HCT-116 xenografted in BALB/C^nu/nu mice, reduced the expression of the proliferation marker Ki67, and significantly affected the expression of cancer-related genes. After incubation with human and mouse liver microsomes, <b>25</b> showed a higher metabolic stability than <b>5</b>. Compound <b>25</b> aims to be a promising lead for the development of colorectal cancer anticancer therapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594536","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 CHD1 Antagonists for PTEN-Deficient Prostate Cancer","authors":"Rebecca L. Johnson, Amanda L. Graboski, Fengling Li, Jacqueline L. Norris-Drouin, William G. Walton, Cheryl H. Arrowsmith, Matthew R. Redinbo, Stephen V. Frye, Lindsey I. James","doi":"10.1021/acs.jmedchem.4c01172","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01172","url":null,"abstract":"CHD1 is a chromodomain-helicase DNA-binding protein that preferentially recognizes di- and trimethylated lysine 4 on histone H3 (H3K4me2/3). Genetic studies have established CHD1 as a synthetic lethal target in phosphatase and tensin homologue (PTEN)-deficient cancers. Despite this attractive therapeutic link, no inhibitors or antagonists of CHD1 have been reported to date. Herein, we report the discovery of UNC10142, a first-in-class small molecule antagonist of the tandem chromodomains of CHD1 that binds with an IC₅₀ of 1.7 ± 0.2 μM. A cocrystal structure revealed a unique binding mode and competition pull-down experiments in cell lysates confirmed endogenous target engagement. Treatment of PTEN-deficient prostate cancer cells with UNC10142 led to a dose-dependent reduction in viability while PTEN-intact prostate cancer cells were unaffected, phenocopying genetic loss of CHD1. Overall, this study demonstrates the ligandability of the CHD1 chromodomains and suggests more potent and selective antagonists could translate to compounds of therapeutic value in PTEN-deficient cancers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596903","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 5-Nitro-N-(3-(trifluoromethyl)phenyl) Pyridin-2-amine as a Novel Pure Androgen Receptor Antagonist against Antiandrogen Resistance","authors":"Huating Wang, Xuwen Wang, Haiyang Zhong, Lvtao Cai, Weitao Fu, Xin Chai, Jianing Liao, Rong Sheng, Luhu Shan, Xiaohong Xu, Lei Xu, Peichen Pan, Tingjun Hou, Dan Li","doi":"10.1021/acs.jmedchem.4c01970","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01970","url":null,"abstract":"The transformation of clinical androgen receptor (AR) antagonists into agonists driven by AR mutations poses a significant challenge in treating prostate cancer (PCa). Novel anti-AR therapeutics combating mutation-induced resistance are required. Herein, by combining structure-based virtual screening and biological evaluation, a high-affinity agonist <b>E10</b> was first discovered. Then guided by the representative conformation of State 1 at the free energy landscape, the structural optimization of <b>E10</b> was performed, and pure AR antagonists <b>EL15</b> (IC₅₀ = 0.94 μM) and <b>EF2</b> (IC₅₀ = 0.30 μM) were successfully identified. Both can antagonize wild-type and variant drug-resistant ARs. Therein, <b>EF2</b> demonstrated potent inhibition of the AR pathway and effectively suppressed tumor growth in a C4–2B xenograft mouse model following oral administration. Further molecular dynamics simulation and mutagenesis studies revealed atomic insights into the mode of action of <b>EF2</b> which may serve as a novel lead compound for developing therapeutics against AR-driven PCa.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594535","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 SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors","authors":"Hang Miao, Yanru Qin, DingLu Shao, Qinghua Chen, Yupeng Pan, Meng Lei, Ruokun Wu, Xinran Ye, Xueyuan Wang, Yongqiang Zhu","doi":"10.1021/acs.jmedchem.4c02169","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02169","url":null,"abstract":"Nuclear export factor chromosome region maintenance 1 (CRM1) mediated the transport of various growth-regulatory proteins and was frequently overexpressed in many hematologic and solid tumors. Selinexor (KPT-330) was the only approved CRM1 inhibitor, but the severe gastrointestinal and central nervous system toxicities limited its clinical application. In this manuscript, a series of novel second-generation CRM1 inhibitors were designed, in which <b>SZJK-0421</b> was a more reversible inhibitor than KPT-330. The treatment of various tumor cells with <b>SZJK-0421</b> significantly inhibited the function of CRM1. <b>SZJK-0421</b> displayed good liver microsome stabilities and pharmacokinetic properties. Most importantly, <b>SZJK-0421</b> reduced the direct damage to the gastrointestinal mucosa, and the brain plasma distribution ratio of <b>SZJK-0421</b> was very low in Sprague-Dawley (SD) rats (3%), which avoided gastrointestinal reactions such as central nausea and vomiting caused by large permeability of blood–brain barrier. In addition, <b>SZJK-0421</b> exhibited strong anticancer efficacy in xenograft models of both solid and hematological tumors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596901","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":"Medicinal Chemistry Education: Emphasize Fundamentals and Skillfully Integrate Knowledge","authors":"Shaoqing Du, Xueping Hu, Craig W. Lindsley, Peng Zhan","doi":"10.1021/acs.jmedchem.4c02622","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02622","url":null,"abstract":"Medicinal chemistry is an interdisciplinary field that aims to discover innovative drugs and synthesize drug molecules at the intersection of chemistry and biology. In the field of medicinal chemistry education, it is essential to establish a robust foundation by emphasizing fundamental principles of chemistry and biology. This strategy not only imparts students with a comprehensive understanding of core concepts but also equips them with the requisite skills to effectively apply this knowledge in their future pursuits. Bioisosteric replacement is a commonly used and effective drug design strategy that involves reactions such as acylation and alkylation. However, this leads to students only mastering these reactions and shying away from more complex ones. As a fundamental component of medicinal chemistry education, a robust foundation in chemistry is imperative. With advancements in organic chemistry, numerous reactions─such as click chemistry, multicomponent reactions, molecular editing (1−5)─and tools─including photocatalysis, biocatalysis, and asymmetric catalysis (6−9)─have emerged. These developments have greatly facilitated progress in medicinal chemistry. By employing click chemistry, we can efficiently synthesize a diverse array of valuable molecules, which is particularly advantageous in the realms of drug design and discovery. Our research group has utilized this approach to identify compounds exhibiting high activity against the main protease of SARS-CoV-2 and its variants. (4) The multicomponent reactions enable the efficient synthesis of a diverse array of compounds throughout the drug discovery process, thereby expediting the screening of potential drug candidates. (10) In the synthesis of isocyanide compounds exhibiting activity against the main protease of SARS-CoV, the Ugi reaction plays a pivotal role. (2) The application of molecular editing techniques enables the rapid synthesis of a diverse array of compounds, thereby expediting the screening process for potential drug candidates. The substitution of a single carbon atom in the pyridine ring with a nitrogen atom led to the development of avanafil, an FDA-approved medication that demonstrated a 20-fold increase in potency. (11) Additionally, photocatalysis, biocatalysis, and asymmetric catalysis represent potent methodologies for the synthesis of intricate pharmaceutical compounds. (6−9) In addition to a robust foundation in chemistry, proficiency in drug design is essential for students pursuing medicinal chemistry. Computer-aided drug design (CADD) serves as a pivotal tool within the realm of drug development. This approach utilizes various technologies, including computer technology, computational chemistry, computational biology, molecular graphics, mathematical statistics, and databases, to explore the interactions between drugs and their respective receptors. The objective is to establish a methodological framework for discovering, designing, and optimizing innovative dr","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589139","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":"Antiplasmodial and Insecticidal Activities of Third-Generation Ivermectin Hybrids","authors":"Parth, Sofia Santana, Catarina Rôla, Carla Bastos Oliveira, Miguel Prudêncio, Kamaljit Singh, Diana Fontinha","doi":"10.1021/acs.jmedchem.4c01606","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01606","url":null,"abstract":"Preclinical and/or clinical studies have demonstrated the potential of Ivermectin (IVM) for malaria control. In order to improve its antiplasmodial activity and build on previous knowledge, we have designed a third generation of hybrid molecules in which selected pharmacophores were appended to the IVM macrolide, while retaining one or both sugar moieties at the C-13 position. Moreover, we synthesized IVM hybrids that contain structural features of potent IVM metabolites. The evaluation of the <i>in vitro</i> antiplasmodial activity of these compounds against <i>Plasmodium berghei</i> pre-erythrocytic stages and <i>Plasmodium falciparum</i> erythrocytic stages identified molecules that displayed enhanced activity against the latter when compared to IVM. Additionally, two IVM intermediates and one IVM hybrid retained the insecticidal activity of the parental molecule, clarifying the contribution of the sugar moieties to this feature. Altogether, these results provide key structure–activity relationships to guide the rational design of new generations of IVM hybrids.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589138","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":"Single Amine or Guanidine Modification on Norvancomycin and Vancomycin to Overcome Multidrug-Resistance through Augmented Lipid II Binding and Increased Membrane Activity","authors":"Xiaolei Bian, Zhifu Chen, Fang Li, Yuanyuan Xie, Yi Li, Youhong Luo, Xiangman Zou, Hui Wang, Jingwen Zhang, Xiaowen Wang, Jinyong Zhang, Dongliang Guan","doi":"10.1021/acs.jmedchem.4c02196","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02196","url":null,"abstract":"Vancomycin and norvancomycin have diminished antibacterial efficacy due to acquired or intrinsic resistance from mutations in the terminal dipeptide of lipid II in Gram-positive bacteria or failure to penetrate into the periplasm in Gram-negative bacteria. Herein, we rationally designed and synthesized a series of vancomycin analogues bearing single amine or guanidine functionality, altering various linkers and modification sites, to combat the resistance. Extensive antibacterial screening was performed to delineate a comprehensive SAR. Many derivatives revitalized the activity in vitro, exhibiting a 4–128-fold or 2–16-fold enhancement against the acquired or intrinsic resistance with lower toxicity. Significantly, the optimal compound <b>4g</b> demonstrated greater pharmacokinetic and pharmacodynamic profiles. Further studies uncovered additional independent and synergistic mechanisms for <b>4g</b>, including the enhanced membrane activity and augmented inhibition of peptidoglycan biosynthesis via increased lipid II binding, highlighting its potential as a future lead candidate to replenish the glycopeptide antibiotic arsenal.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589143","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 Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors","authors":"Bin Tan, Xueying Liang, Ahmadullah Ansari, Prakash Jadhav, Haozhou Tan, Kan Li, Francesc Xavier Ruiz, Eddy Arnold, Xufang Deng, Jun Wang","doi":"10.1021/acs.jmedchem.4c01872","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01872","url":null,"abstract":"The COVID-19 pandemic is caused by SARS-CoV-2, a highly transmissible and pathogenic RNA betacoronavirus. Like other RNA viruses, SARS-CoV-2 continues to evolve with or without drug selection pressure, and many variants have emerged since the beginning of the pandemic. The papain-like protease, PL^pro, is a cysteine protease that cleaves viral polyproteins as well as ubiquitin and ISG15 modifications from host proteins. Leveraging our recently discovered Val70^Ub binding site in PL^pro, we designed covalent PL^pro inhibitors by connecting cysteine reactive warheads to the biarylphenyl PL^pro inhibitors via flexible linkers. Several leads displayed potent enzymatic inhibition (IC₅₀ = 0.1–0.3 μM) and antiviral activity (EC₅₀ = 0.09–0.96 μM). Fumaramide inhibitors <b>Jun13567 (15)</b>, <b>Jun13728 (16)</b>, and <b>Jun13714 (18)</b> showed favorable <i>in vivo</i> pharmacokinetic properties with intraperitoneal injection. The X-ray crystal structure of PL^pro with <b>Jun13567 (15)</b> validated our design strategy, revealing covalent conjugation between the catalytic Cys111 and the fumaramide warhead. The results suggest these covalent PL^pro inhibitors are promising SARS-CoV-2 antiviral drug candidates.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580384","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 Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL)","authors":"Rebecca A. Gallego, Stephanie Scales, Chad Toledo, Marin Auth, Louise Bernier, Madeline Berry, Sonja Brun, Loanne Chung, Carl Davis, Wade Diehl, Klaus Dress, Koleen Eisele, Jeff Elleraas, Jason Ewanicki, Yvette Fobian, Samantha Greasley, Eric C. Greenwald, Ted W. Johnson, Penney Khamphavong, Jennifer Lafontaine, Jian Li, Angelica Linton, Michael Maestre, Nichol Miller, Anwar Murtaza, Ryan L. Patman, Casey L. Quinlan, Dana J. Ramms, Paul Richardson, Neal Sach, Romelia Salomon-Ferrer, Francisco Silva, Sergei Timofeevski, Phuong Tran, Michelle Tran-Dubé, Fen Wang, Wei Wang, Martin Wythes, Shouliang Yang, Aihua Zou, Todd VanArsdale, Indrawan McAlpine","doi":"10.1021/acs.jmedchem.4c01659","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01659","url":null,"abstract":"By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580383","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}