Pub Date : 2025-01-17DOI: 10.1016/j.ejmech.2025.117282
Christina Karhan, Svenja M. Sake, Antonia P. Gunesch, Christina Grethe, Benedikt Hellwinkel, Natalie M. Köhler, Alexander F. Kiefer, Uladzislau Hapko, Andreas M. Kany, Thomas Pietschmann, Anna K.H. Hirsch
Acute respiratory diseases in humans can be caused by various viral pathogens such as respiratory syncytial virus (RSV), human coronavirus 229E (hCoV-229E), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To prevent severe cases by an early treatment, one effective strategy is to inhibit viral infection at the entry stage of the replication cycle. However, there is a lack of efficient, FDA-approved small molecule drugs targeting these pathogens. Previously, we identified two dual RSV/hCoV-229E small molecule inhibitors with activity in the single-digit micromolar range. In this study, we focused on a structure-guided optimization approach of the more promising prototype addressing activity, cell viability, selectivity, solubility and metabolic stability. We present valuable insights into the structure–activity relationship (SAR), and report the discovery of a sub micromolar RSV entry inhibitor, a dual RSV/CoV-229E inhibitor and a highly potent compound against hCoV-229E.
{"title":"Unlocking the Antiviral Arsenal: Structure-Guided Optimization of Small-Molecule Inhibitors against RSV and hCoV-229E","authors":"Christina Karhan, Svenja M. Sake, Antonia P. Gunesch, Christina Grethe, Benedikt Hellwinkel, Natalie M. Köhler, Alexander F. Kiefer, Uladzislau Hapko, Andreas M. Kany, Thomas Pietschmann, Anna K.H. Hirsch","doi":"10.1016/j.ejmech.2025.117282","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117282","url":null,"abstract":"Acute respiratory diseases in humans can be caused by various viral pathogens such as respiratory syncytial virus (RSV), human coronavirus 229E (hCoV-229E), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To prevent severe cases by an early treatment, one effective strategy is to inhibit viral infection at the entry stage of the replication cycle. However, there is a lack of efficient, FDA-approved small molecule drugs targeting these pathogens. Previously, we identified two dual RSV/hCoV-229E small molecule inhibitors with activity in the single-digit micromolar range. In this study, we focused on a structure-guided optimization approach of the more promising prototype addressing activity, cell viability, selectivity, solubility and metabolic stability. We present valuable insights into the structure–activity relationship (SAR), and report the discovery of a sub micromolar RSV entry inhibitor, a dual RSV/CoV-229E inhibitor and a highly potent compound against hCoV-229E.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"55 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.ejmech.2025.117287
Yizhen Jiang, Yutong Wang, Feijing Su, Yaqin Hou, Wen Liao, Baichuan Li, Wuyu Mao
NEK2, a serine/threonine protein kinase, is integral to mitotic events such as centrosome duplication and separation, microtubule stabilization, spindle assembly checkpoint, and kinetochore attachment. However, NEK2 overexpression leads to centrosome amplification and chromosomal instability, which are significantly associated with various malignancies, including liver, breast, and non-small cell lung cancer. This overexpression could facilitate tumor development and confer resistance to therapy by promoting aberrant cell division and centrosome amplification. Consequently, inhibiting NEK2 is considered as a promising strategy for oncological therapy. To date, no small molecule NEK2-specific inhibitors have advanced into clinical trials, highlighting the necessity for optimized design and the deployment of innovative technologies. In this review, we will provide a comprehensive summary of the chemical structure, biological functions, and disease associations of NEK2, focusing on the existing NEK2 small molecule inhibitors, especially their structure-activity relationships, limitations, and research strategies. Our objective is to provide valuable insights for the future development of NEK2 inhibitors and analysis of challenges faced in translating these findings into clinical applications.
{"title":"Insights into NEK2 inhibitors as antitumor agents: From mechanisms to potential therapeutics","authors":"Yizhen Jiang, Yutong Wang, Feijing Su, Yaqin Hou, Wen Liao, Baichuan Li, Wuyu Mao","doi":"10.1016/j.ejmech.2025.117287","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117287","url":null,"abstract":"NEK2, a serine/threonine protein kinase, is integral to mitotic events such as centrosome duplication and separation, microtubule stabilization, spindle assembly checkpoint, and kinetochore attachment. However, NEK2 overexpression leads to centrosome amplification and chromosomal instability, which are significantly associated with various malignancies, including liver, breast, and non-small cell lung cancer. This overexpression could facilitate tumor development and confer resistance to therapy by promoting aberrant cell division and centrosome amplification. Consequently, inhibiting NEK2 is considered as a promising strategy for oncological therapy. To date, no small molecule NEK2-specific inhibitors have advanced into clinical trials, highlighting the necessity for optimized design and the deployment of innovative technologies. In this review, we will provide a comprehensive summary of the chemical structure, biological functions, and disease associations of NEK2, focusing on the existing NEK2 small molecule inhibitors, especially their structure-activity relationships, limitations, and research strategies. Our objective is to provide valuable insights for the future development of NEK2 inhibitors and analysis of challenges faced in translating these findings into clinical applications.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.ejmech.2025.117288
Yi Wei, Xiaoling He, Zhiwu Long, Yi Le, Li Liu, Longjia Yan
Temozolomide, a widely used alkylating agent for glioblastoma treatment, faces significant challenges due to the development of resistance, which severely impacts patient survival. This underscores the urgent need for novel strategies to overcome this barrier. Focal adhesion kinase (FAK), an intracellular non-receptor tyrosine kinase, is highly expressed in glioblastoma cells and has been identified as a promising therapeutic target for anti-glioblastoma drug development. In this study, we report design and synthesis of a novel series of diaminopyrimidine-based small molecules that concurrently target both FAK and DNA. Among these compounds, 9f emerged as a potent dual inhibitor, demonstrating exceptional inhibitory activity against FAK (IC50 = 0.815 nM) and DNA, as well as remarkable antiproliferative effects on glioblastoma cell lines U87-MG (IC50 = 15 nM) and U251 (IC50 = 20 nM). Furthermore, compound 9f significantly induced apoptosis in U87-MG cells and caused cell cycle arrest at the G2/M phase. Notably, in a U87-MG xenograft model, compound 9f exhibited superior antitumor efficacy. These findings underscore the potential of FAK/DNA inhibitors as a promising approach to overcome resistance.
{"title":"Discovery of Noncovalent Diaminopyrimidine-based Inhibitors for Glioblastoma via a Dual FAK/DNA Targeting Strategy","authors":"Yi Wei, Xiaoling He, Zhiwu Long, Yi Le, Li Liu, Longjia Yan","doi":"10.1016/j.ejmech.2025.117288","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117288","url":null,"abstract":"Temozolomide, a widely used alkylating agent for glioblastoma treatment, faces significant challenges due to the development of resistance, which severely impacts patient survival. This underscores the urgent need for novel strategies to overcome this barrier. Focal adhesion kinase (FAK), an intracellular non-receptor tyrosine kinase, is highly expressed in glioblastoma cells and has been identified as a promising therapeutic target for anti-glioblastoma drug development. In this study, we report design and synthesis of a novel series of diaminopyrimidine-based small molecules that concurrently target both FAK and DNA. Among these compounds, <strong>9f</strong> emerged as a potent dual inhibitor, demonstrating exceptional inhibitory activity against FAK (IC<sub>50</sub> = 0.815 nM) and DNA, as well as remarkable antiproliferative effects on glioblastoma cell lines U87-MG (IC<sub>50</sub> = 15 nM) and U251 (IC<sub>50</sub> = 20 nM). Furthermore, compound <strong>9f</strong> significantly induced apoptosis in U87-MG cells and caused cell cycle arrest at the G2/M phase. Notably, in a U87-MG xenograft model, compound <strong>9f</strong> exhibited superior antitumor efficacy. These findings underscore the potential of FAK/DNA inhibitors as a promising approach to overcome resistance.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cholestatic liver disease (CLD) represents a significant and growing public health concern, and there is a lack of effective therapeutic drug in clinical practice. Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for CLD. In this study, a series of novel imidazolidinone PPARα/δ agonists were developed, and the preferred compound 8 displayed potent and well-balanced agonistic activity. Compound 8 showed high selectivity over other related nuclear receptors and effectively regulated the PPARα/δ target genes expression in mice. Notably, compound 8 demonstrated good pharmacokinetic profiles and potent in vivo anti-CLD effects. Collectively, compound 8 holds promise for developing an anti-CLD agent.
{"title":"Design, Synthesis, and Biological Evaluation of Imidazolidinone Derivatives as Potent PPARα/δ Agonists for the Treatment of Cholestatic Liver Diseases","authors":"Zhuoxin Fu, Xin Liu, Wenhui Yu, Yufan Kuang, Fengqin Wang, Zhiqiang Qian, Qinglong Xu, Liang Dai, Zhiqi Feng","doi":"10.1016/j.ejmech.2025.117284","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117284","url":null,"abstract":"Cholestatic liver disease (CLD) represents a significant and growing public health concern, and there is a lack of effective therapeutic drug in clinical practice. Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for CLD. In this study, a series of novel imidazolidinone PPARα/δ agonists were developed, and the preferred compound <strong>8</strong> displayed potent and well-balanced agonistic activity. Compound <strong>8</strong> showed high selectivity over other related nuclear receptors and effectively regulated the PPARα/δ target genes expression in mice. Notably, compound <strong>8</strong> demonstrated good pharmacokinetic profiles and potent <em>in vivo</em> anti-CLD effects. Collectively, compound <strong>8</strong> holds promise for developing an anti-CLD agent.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"95 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.ejmech.2025.117272
Jing-Ying Liu, Hong-En Zhang, Cheng Wang, Ping-Fan Zhang, Yun-Gen Xu, Lei Shi, Li-Ping Sun
The bromodomain-containing protein 4 (BRD4) is an epigenetic regulatory 'reader' belonging to the bromodomain and extra-terminal domain (BET) family. Several studies have demonstrated that the high expression of BRD4 is closely related to the occurrence and development of various cancers, so BRD4 has become a promising target for cancer treatment. However, there are no drugs targeting BRD4 available on the market, the development of novel BRD4 inhibitors is of great significance. This paper describes a series of triazolopyridine derivatives exhibiting favorable BRD4 inhibitory activity, which have not been reported before. Among them, the representative compound 12m showed potent BRD4 BD1 inhibitory activity, of which the inhibition rate is better than the other compounds. In MV4-11 cell line, compound 12m also showed excellent anti-cancer activity (IC50 = 0.02 μM), which is superior to (+)-JQ1 (IC50 = 0.03 μM). Through molecular docking, it was discovered that compound 12m could combine with the acetyl-lysine binding site of BRD4 BD1 and form a hydrogen bond with a crucial amino acid residue Asn140. Additionally, compound 12m was found to have good metabolic stability with a clearance rate of only 0.3 μL/min/nm in mouse liver microsomes. Apoptosis experiments demonstrated that compound 12m induced apoptosis better than (+)-JQ1 at the same concentration, and the apoptosis rate of compound 12m increased from 43.2% to 83.2%. Subsequent in vivo pharmacokinetic testing of compound 12m in ICR mice yielded a good oral absorption and utilization of compound 12m (F = 44.8%). The results indicate that triazolopyridine is an outstanding skeleton for developing novel BRD4 inhibitors, and compound 12m is a promising lead compound for further optimization and extensive clinical development.
{"title":"Design, synthesis, and antitumor evaluation of triazolopyridine derivatives as novel inhibitors for BRD4","authors":"Jing-Ying Liu, Hong-En Zhang, Cheng Wang, Ping-Fan Zhang, Yun-Gen Xu, Lei Shi, Li-Ping Sun","doi":"10.1016/j.ejmech.2025.117272","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117272","url":null,"abstract":"The bromodomain-containing protein 4 (BRD4) is an epigenetic regulatory 'reader' belonging to the bromodomain and extra-terminal domain (BET) family. Several studies have demonstrated that the high expression of BRD4 is closely related to the occurrence and development of various cancers, so BRD4 has become a promising target for cancer treatment. However, there are no drugs targeting BRD4 available on the market, the development of novel BRD4 inhibitors is of great significance. This paper describes a series of triazolopyridine derivatives exhibiting favorable BRD4 inhibitory activity, which have not been reported before. Among them, the representative compound <strong>12m</strong> showed potent BRD4 BD1 inhibitory activity, of which the inhibition rate is better than the other compounds. In MV4-11 cell line, compound <strong>12m</strong> also showed excellent anti-cancer activity (IC<sub>50</sub> = 0.02 μM), which is superior to (+)-<strong>JQ1</strong> (IC<sub>50</sub> = 0.03 μM). Through molecular docking, it was discovered that compound <strong>12m</strong> could combine with the acetyl-lysine binding site of BRD4 BD1 and form a hydrogen bond with a crucial amino acid residue Asn140. Additionally, compound <strong>12m</strong> was found to have good metabolic stability with a clearance rate of only 0.3 μL/min/nm in mouse liver microsomes. Apoptosis experiments demonstrated that compound <strong>12m</strong> induced apoptosis better than (+)-<strong>JQ1</strong> at the same concentration, and the apoptosis rate of compound <strong>12m</strong> increased from 43.2% to 83.2%. Subsequent <em>in vivo</em> pharmacokinetic testing of compound <strong>12m</strong> in ICR mice yielded a good oral absorption and utilization of compound <strong>12m</strong> (F = 44.8%). The results indicate that triazolopyridine is an outstanding skeleton for developing novel BRD4 inhibitors, and compound <strong>12m</strong> is a promising lead compound for further optimization and extensive clinical development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Exosomes are critical mediators of cell-to-cell communication in physiological and pathological processes, due to their ability to deliver a variety of bioactive molecules. Tumor-derived exosomes (TDEs), in particular, carry carcinogenic molecules that contribute to tumor progression, metastasis, immune escape, and drug resistance. Thus, TDE inhibition has emerged as a promising strategy to combat cancer. In this review, we discuss the key mechanisms of TDE biogenesis and secretion, emphasizing their implications in tumorigenesis and cancer progression. Moreover, we provide an overview of small-molecule TDE inhibitors that target specific biogenesis and/or secretion pathways, highlighting their potential use in cancer treatment. Lastly, we present the existing obstacles and propose corresponding remedies for the future development of TDE inhibitors.
{"title":"Insights into tumor-derived exosome inhibition in cancer therapy","authors":"Ziwei Tang, Cheng Chen, Chen Zhou, Zhouyan Liu, Tong Li, Ye Zhang, Yanyan Feng, Chenglei Gu, Shijia Li, Jichao Chen","doi":"10.1016/j.ejmech.2025.117278","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117278","url":null,"abstract":"Exosomes are critical mediators of cell-to-cell communication in physiological and pathological processes, due to their ability to deliver a variety of bioactive molecules. Tumor-derived exosomes (TDEs), in particular, carry carcinogenic molecules that contribute to tumor progression, metastasis, immune escape, and drug resistance. Thus, TDE inhibition has emerged as a promising strategy to combat cancer. In this review, we discuss the key mechanisms of TDE biogenesis and secretion, emphasizing their implications in tumorigenesis and cancer progression. Moreover, we provide an overview of small-molecule TDE inhibitors that target specific biogenesis and/or secretion pathways, highlighting their potential use in cancer treatment. Lastly, we present the existing obstacles and propose corresponding remedies for the future development of TDE inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.ejmech.2025.117280
Shujin Guo, Yingying Zhao, Yan Yuan, Yang Liao, Xuepan Jiang, Lin Wang, Wei Lu, Jianyou Shi
Macrophage migration inhibitory factor (MIF) functions as a critical cytokine regulating inflammatory and immune responses. Extensive research has demonstrated its involvement in the progression of various cancers, autoimmune diseases, and inflammatory disorders, establishing it as a pivotal target for anti-inflammatory and anticancer interventions. Therapeutic strategies aimed at MIF primarily focus on suppressing its activity through small molecule inhibitors and natural compounds. This review synthesizes current knowledge on MIF, encompassing its structural characteristics, enzymatic functions, signaling pathways, and roles in disease pathogenesis. Additionally, it provides an in-depth analysis of recent advancements in MIF inhibitor development, including design methodologies, structure-activity relationships, advanced eutectic analysis techniques, and key experimental findings. The discussion aims to support the development of safer, more effective, and highly selective small molecule inhibitors targeting MIF.
{"title":"Progress in the development of Macrophage Migration Inhibitory Factor small-molecule inhibitors","authors":"Shujin Guo, Yingying Zhao, Yan Yuan, Yang Liao, Xuepan Jiang, Lin Wang, Wei Lu, Jianyou Shi","doi":"10.1016/j.ejmech.2025.117280","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117280","url":null,"abstract":"Macrophage migration inhibitory factor (MIF) functions as a critical cytokine regulating inflammatory and immune responses. Extensive research has demonstrated its involvement in the progression of various cancers, autoimmune diseases, and inflammatory disorders, establishing it as a pivotal target for anti-inflammatory and anticancer interventions. Therapeutic strategies aimed at MIF primarily focus on suppressing its activity through small molecule inhibitors and natural compounds. This review synthesizes current knowledge on MIF, encompassing its structural characteristics, enzymatic functions, signaling pathways, and roles in disease pathogenesis. Additionally, it provides an in-depth analysis of recent advancements in MIF inhibitor development, including design methodologies, structure-activity relationships, advanced eutectic analysis techniques, and key experimental findings. The discussion aims to support the development of safer, more effective, and highly selective small molecule inhibitors targeting MIF.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.ejmech.2025.117268
Yufeng An, Xinya Lv, Shidi Xu, Heqing Li, Pengwu Zheng, Wufu Zhu, Linxiao Wang
The epidermal growth factor receptor (EGFR) is a pivotal member of the epidermal growth factor receptor family, exerting crucial regulatory influence on cellular physiological processes, particularly in relation to cell growth, proliferation, and differentiation. In recent years, numerous EGFR inhibitors have been introduced to the market; unfortunately, the effectiveness of single-target EGFR inhibitors has been compromised due to the development of drug resistance caused by EGFR mutations. Despite attempts by some researchers to address this issue through combination therapy with two or more drugs, instances of dose-limiting toxicities have been observed. Consequently, EGFR dual-target inhibitors have emerged as a burgeoning field in cancer treatment, offering a novel therapeutic option for solid tumors with the added benefits of reduced risk of resistance, lower dosage requirements, diminished toxicity profiles, and enhanced efficacy. At present, a series of EGFR dual-target inhibitors with diverse structures have been developed successively. In this study, we initially investigated the pyrimidine-based EGFR dual-target inhibitors that have been reported in the past two decades and categorized them into aminopyrimidine derivatives and heterocyclic pyrimidine derivatives with increased molecular complexity. Subsequently, we comprehensively summarized the biological activity and structure-activity relationship of this class of inhibitors in the context of cancer therapy, while also exploring potential opportunities and challenges associated with their application in this field. The present study provides a partial framework to guide future endeavors in drug development.
{"title":"Pyrimidine-based dual-target inhibitors targeting epidermal growth factor receptor for overcoming drug resistance in cancer therapy(2006-present)","authors":"Yufeng An, Xinya Lv, Shidi Xu, Heqing Li, Pengwu Zheng, Wufu Zhu, Linxiao Wang","doi":"10.1016/j.ejmech.2025.117268","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117268","url":null,"abstract":"The epidermal growth factor receptor (EGFR) is a pivotal member of the epidermal growth factor receptor family, exerting crucial regulatory influence on cellular physiological processes, particularly in relation to cell growth, proliferation, and differentiation. In recent years, numerous EGFR inhibitors have been introduced to the market; unfortunately, the effectiveness of single-target EGFR inhibitors has been compromised due to the development of drug resistance caused by EGFR mutations. Despite attempts by some researchers to address this issue through combination therapy with two or more drugs, instances of dose-limiting toxicities have been observed. Consequently, EGFR dual-target inhibitors have emerged as a burgeoning field in cancer treatment, offering a novel therapeutic option for solid tumors with the added benefits of reduced risk of resistance, lower dosage requirements, diminished toxicity profiles, and enhanced efficacy. At present, a series of EGFR dual-target inhibitors with diverse structures have been developed successively. In this study, we initially investigated the pyrimidine-based EGFR dual-target inhibitors that have been reported in the past two decades and categorized them into aminopyrimidine derivatives and heterocyclic pyrimidine derivatives with increased molecular complexity. Subsequently, we comprehensively summarized the biological activity and structure-activity relationship of this class of inhibitors in the context of cancer therapy, while also exploring potential opportunities and challenges associated with their application in this field. The present study provides a partial framework to guide future endeavors in drug development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.ejmech.2025.117270
Mariam T. Sayed, Mohamed F. Mady
Organophosphorus compounds, characterized by the incorporation of phosphorus into organic molecules, play a critical role in various fields such as medicine, agriculture, and industry. Their unique electronic properties and versatility make them essential in developing therapeutic agents, pesticides, and materials. One prominent class of organophosphorus compounds is organophosphorus heterocycles, which combine the benefits of both phosphorus and cyclic structures. Triazoles, a class of nitrogen-containing heterocyclic compounds, are particularly notable for their broad biological activities, including anticancer, antiviral, antibacterial, and antioxidant effects. Traditional methods for synthesizing triazoles often encounter challenges such as low yields and non-selective products, whereas click chemistry provides a more efficient and reliable alternative. The copper-catalyzed azide-alkyne [3+2] cycloaddition, a cornerstone of click chemistry, allows for the rapid and selective formation of triazoles under mild conditions. When functionalized with organophosphorus groups, triazoles not only retain but often enhance their biological activities, improving their potency, selectivity, and stability. This review covers the synthesis of organophosphorus-functionalized triazoles via click chemistry and explores their molecular structure, including the coordination chemistry of these compounds. The behavior and interactions of these organophosphorus derivatives with various metal ions are also addressed, as these interactions significantly influence their chemical reactivity, stability, and bioactivity.
{"title":"A Review of Click Chemistry in the Synthesis of Organophosphorus Triazoles and Their Biological Activities","authors":"Mariam T. Sayed, Mohamed F. Mady","doi":"10.1016/j.ejmech.2025.117270","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117270","url":null,"abstract":"Organophosphorus compounds, characterized by the incorporation of phosphorus into organic molecules, play a critical role in various fields such as medicine, agriculture, and industry. Their unique electronic properties and versatility make them essential in developing therapeutic agents, pesticides, and materials. One prominent class of organophosphorus compounds is organophosphorus heterocycles, which combine the benefits of both phosphorus and cyclic structures. Triazoles, a class of nitrogen-containing heterocyclic compounds, are particularly notable for their broad biological activities, including anticancer, antiviral, antibacterial, and antioxidant effects. Traditional methods for synthesizing triazoles often encounter challenges such as low yields and non-selective products, whereas click chemistry provides a more efficient and reliable alternative. The copper-catalyzed azide-alkyne [3+2] cycloaddition, a cornerstone of click chemistry, allows for the rapid and selective formation of triazoles under mild conditions. When functionalized with organophosphorus groups, triazoles not only retain but often enhance their biological activities, improving their potency, selectivity, and stability. This review covers the synthesis of organophosphorus-functionalized triazoles via click chemistry and explores their molecular structure, including the coordination chemistry of these compounds. The behavior and interactions of these organophosphorus derivatives with various metal ions are also addressed, as these interactions significantly influence their chemical reactivity, stability, and bioactivity.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AMP-activated protein kinase (AMPK), a heterotrimeric serine-threonine kinase, has been identified as a promising target for regulating vascular remodeling in pulmonary arterial hypertension (PAH) due to its capacity to promote proliferation, autophagy, and anti-apoptosis in pulmonary artery smooth muscle cells (PASMCs). However, research into AMPK inhibitors is very limited. Herein, a virtual screening strategy was employed to identify CHEMBLE3780091 as a lead compound for a series of novel AMPK inhibitors by exploring the structure-activity relationship around a specific pyridine-2-one scaffold. Subsequently, the most promising 13a was observed to exhibit excellent AMPK inhibitory activity and favorable anti-proliferative activity against PASMCs through the inhibition of the AMPK signaling pathway in vitro. Moreover, compound 13a significantly reduced right ventricular systolic pressure, attenuated vascular remodeling, and improved right heart function in hypoxia-induced PAH rats in vivo. In conclusion, this study provides a novel and potential lead compound for the study of AMPK inhibitors and a new direction for the development of PAH drugs that focus on improving vascular remodeling.
{"title":"A novel pyridine-2-one AMPK inhibitor: discovery, mechanism, and in vivo evaluation in a hypoxic pulmonary arterial hypertension rat model","authors":"Wenhua Tan, Yu Wang, Mengqi Li, Congke Zhao, Yuanbo Hu, Ruizhe Gao, Zhuo Chen, Liqing Hu, Qianbin Li","doi":"10.1016/j.ejmech.2025.117266","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117266","url":null,"abstract":"AMP-activated protein kinase (AMPK), a heterotrimeric serine-threonine kinase, has been identified as a promising target for regulating vascular remodeling in pulmonary arterial hypertension (PAH) due to its capacity to promote proliferation, autophagy, and anti-apoptosis in pulmonary artery smooth muscle cells (PASMCs). However, research into AMPK inhibitors is very limited. Herein, a virtual screening strategy was employed to identify CHEMBLE3780091 as a lead compound for a series of novel AMPK inhibitors by exploring the structure-activity relationship around a specific pyridine-2-one scaffold. Subsequently, the most promising <strong>13a</strong> was observed to exhibit excellent AMPK inhibitory activity and favorable anti-proliferative activity against PASMCs through the inhibition of the AMPK signaling pathway <em>in vitro</em>. Moreover, compound <strong>13a</strong> significantly reduced right ventricular systolic pressure, attenuated vascular remodeling, and improved right heart function in hypoxia-induced PAH rats <em>in vivo</em>. In conclusion, this study provides a novel and potential lead compound for the study of AMPK inhibitors and a new direction for the development of PAH drugs that focus on improving vascular remodeling.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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