Pub Date : 2025-02-25DOI: 10.1016/j.ejmech.2025.117400
Yanping Zeng, Jian Xiao, Li Shi, Yangsha Li, Yuanxin Xu, Jiayun Zhou, Xiao Dong, Haiyang Hou, Chao Zhong, Gang Cheng, Yi Chen, Naixia Zhang, Yanfen Fang, Youhong Hu
The authors regret the incorrect placement in Fig. 4 and the molar ratios of LC3B to 33R or 34R in figure captions for Fig. 5A and B were incorrect.
{"title":"Corrigendum to “Discovery of 2,4-Quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations”[Eur. J. Med. Chem. 287 (2025) 117293]","authors":"Yanping Zeng, Jian Xiao, Li Shi, Yangsha Li, Yuanxin Xu, Jiayun Zhou, Xiao Dong, Haiyang Hou, Chao Zhong, Gang Cheng, Yi Chen, Naixia Zhang, Yanfen Fang, Youhong Hu","doi":"10.1016/j.ejmech.2025.117400","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117400","url":null,"abstract":"The authors regret the incorrect placement in Fig. 4 and the molar ratios of LC3B to 33R or 34R in figure captions for Fig. 5A and B were incorrect.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496057","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117440
Han Wu , Yixin Ren , Jungan Zhang , Jingsu Xue , Lulu Chen , Hongtong Chen , Xinyi Yang , Hao Wang
UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a metalloprotein that utilizes zinc as a cofactor. LpxC plays a crucial role in catalyzing the synthesis of Lipid A, a major component of the outer membrane lipopolysaccharide in Gram-negative (G-) bacteria, and LpxC shares no common amino acid sequence with various mammalian enzyme proteins. LpxC is essential for the survival of Gram-negative bacteria, making it a promising target for the antibacterial drug development. In recent years, numerous LpxC inhibitors have been reported, which can be broadly categorized into hydroxamic acid and non-hydroxamic acid based on their structural characteristics. Although no LpxC inhibitors are currently available on the market, several candidate small molecules are anticipated to enter clinical trials. The current manuscript offers a comprehensive review of the structures, enzyme catalytic mechanisms, and research progress of novel LpxC inhibitors, with the objective of providing insights and directions for future research in the development of LpxC inhibitors as new antibacterial agents.
{"title":"Research progress of LpxC inhibitor on Gram-negative bacteria","authors":"Han Wu , Yixin Ren , Jungan Zhang , Jingsu Xue , Lulu Chen , Hongtong Chen , Xinyi Yang , Hao Wang","doi":"10.1016/j.ejmech.2025.117440","DOIUrl":"10.1016/j.ejmech.2025.117440","url":null,"abstract":"<div><div>UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a metalloprotein that utilizes zinc as a cofactor. LpxC plays a crucial role in catalyzing the synthesis of Lipid A, a major component of the outer membrane lipopolysaccharide in Gram-negative (G-) bacteria, and LpxC shares no common amino acid sequence with various mammalian enzyme proteins. LpxC is essential for the survival of Gram-negative bacteria, making it a promising target for the antibacterial drug development. In recent years, numerous LpxC inhibitors have been reported, which can be broadly categorized into hydroxamic acid and non-hydroxamic acid based on their structural characteristics. Although no LpxC inhibitors are currently available on the market, several candidate small molecules are anticipated to enter clinical trials. The current manuscript offers a comprehensive review of the structures, enzyme catalytic mechanisms, and research progress of novel LpxC inhibitors, with the objective of providing insights and directions for future research in the development of LpxC inhibitors as new antibacterial agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117440"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486371","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 : 2025-02-25DOI: 10.1016/j.ejmech.2025.117436
Yajing Zhang , Rong Huang , Xueqin Hu , Nan Zheng , Lei Geng , Zequn Yin , Yajun Duan , Qin Wang , Chenzhong Liao , Xiaoxiao Yang , Zhouling Xie
Factor XIa (FXIa) has emerged as a promising target for novel anticoagulant development since inhibiting it can reduce thrombosis without significant bleeding risks. Despite a few FXIa inhibitors entering clinical trials, none have been approved for the market yet. Here, we present highly selective and orally bioavailable FXIa inhibitors derived from compound 1, 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one. Structure-activity relationship studies led to the discovery of promising 1-(pyridin-2-ylmethyl)pyridin-2(1H)-one-based FXIa inhibitors 37, 39b, 43, and 46b, which exhibited enhanced FXIa potency and selectivity compared to asundexian, an FXIa inhibitor in phase III clinical trials. Their anticoagulant activity was also comparable to or greater than that of asundexian. Compound 43 significantly reduced thrombosis in both FeCl3-induced mouse and rabbit arterial thrombosis models, demonstrating superior efficacy compared to asundexian. Importantly, 43 did not increase bleeding risks and exhibited a favorable safety profile in mice, suggesting its potential as a promising FXIa inhibitor for the treatment of thrombosis.
{"title":"Discovery of potent, highly selective, and orally bioavailable factor XIa inhibitors for anticoagulant therapy","authors":"Yajing Zhang , Rong Huang , Xueqin Hu , Nan Zheng , Lei Geng , Zequn Yin , Yajun Duan , Qin Wang , Chenzhong Liao , Xiaoxiao Yang , Zhouling Xie","doi":"10.1016/j.ejmech.2025.117436","DOIUrl":"10.1016/j.ejmech.2025.117436","url":null,"abstract":"<div><div>Factor XIa (FXIa) has emerged as a promising target for novel anticoagulant development since inhibiting it can reduce thrombosis without significant bleeding risks. Despite a few FXIa inhibitors entering clinical trials, none have been approved for the market yet. Here, we present highly selective and orally bioavailable FXIa inhibitors derived from compound <strong>1</strong>, 4-(5-chloro-2-(1<em>H</em>-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1<em>H</em>)-one. Structure-activity relationship studies led to the discovery of promising 1-(pyridin-2-ylmethyl)pyridin-2(1<em>H</em>)-one-based FXIa inhibitors <strong>37</strong>, <strong>39b</strong>, <strong>43</strong>, and <strong>46b</strong>, which exhibited enhanced FXIa potency and selectivity compared to asundexian, an FXIa inhibitor in phase III clinical trials. Their anticoagulant activity was also comparable to or greater than that of asundexian. Compound <strong>43</strong> significantly reduced thrombosis in both FeCl<sub>3</sub>-induced mouse and rabbit arterial thrombosis models, demonstrating superior efficacy compared to asundexian. Importantly, <strong>43</strong> did not increase bleeding risks and exhibited a favorable safety profile in mice, suggesting its potential as a promising FXIa inhibitor for the treatment of thrombosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117436"},"PeriodicalIF":6.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485987","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}
Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach in the treatment of chronic HBV infection. In the quest for effective therapeutics against chronic Hepatitis B virus (HBV) infection, we employed a novel binding site occupancy strategy to develop novel 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV capsid assembly modulators (CAMs). Our diversity modification approach led to the identification of compound 17e, which demonstrated remarkable anti-HBV activity with an EC50 of 0.033 μM in HepAD38 cells. Molecular insights obtained through docking and dynamics simulations have provided a comprehensive understanding of the hydrogen bonding interactions between 17e and crucial residues of the HBV core protein, while also revealing the occupation of a novel binding site by the cyclopropyl group, thereby elucidating its inhibitory mechanism. Although 17e exhibited robust metabolic stability in plasma, it underwent rapid metabolism in human liver microsomes. This study underscores the potential of CP-TBA derivatives in crafting the next generation of HBV CAMs with enhanced activity and druggability.
{"title":"Design and biochemical evaluation of 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV capsid assembly modulators targeting a novel binding site","authors":"Mei Wang, Yutong Dou, Aixin Li, Zechun Yang, Minghui Liang, Yuanyuan Liu, Yong Xie, Liyan Wang, Yuqing Cai, Yunfu Chen, Peng Xue, Xin Wang, Zhuanchang Wu, Peng Zhan, Haiyong Jia","doi":"10.1016/j.ejmech.2025.117441","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117441","url":null,"abstract":"Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach in the treatment of chronic HBV infection. In the quest for effective therapeutics against chronic Hepatitis B virus (HBV) infection, we employed a novel binding site occupancy strategy to develop novel 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV capsid assembly modulators (CAMs). Our diversity modification approach led to the identification of compound <strong>17e</strong>, which demonstrated remarkable anti-HBV activity with an EC<sub>50</sub> of 0.033 μM in HepAD38 cells. Molecular insights obtained through docking and dynamics simulations have provided a comprehensive understanding of the hydrogen bonding interactions between <strong>17e</strong> and crucial residues of the HBV core protein, while also revealing the occupation of a novel binding site by the cyclopropyl group, thereby elucidating its inhibitory mechanism. Although <strong>17e</strong> exhibited robust metabolic stability in plasma, it underwent rapid metabolism in human liver microsomes. This study underscores the potential of CP-TBA derivatives in crafting the next generation of HBV CAMs with enhanced activity and druggability.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477673","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 : 2025-02-24DOI: 10.1016/j.ejmech.2025.117445
Małgorzata Lobka, Izabela Siekierska, Piotr Chyży, Michał Burmistrz, Julia Macyszyn, Renata Grzela, Monika Wojciechowska, Joanna Trylska
To address the challenge of antimicrobial resistance, we investigated new antibacterial peptides based on lysine- and leucine-rich sequences. We stabilised their membrane-active secondary structures by applying hydrocarbon stapling at sequence positions i and i+4. Stapling improved peptide structural stability in both aqueous and lipid environments, regardless of the staple position. It also enhanced antibacterial efficiency against both gram-negative and gram-positive bacteria, including antibiotic-resistant strains, with minimum inhibitory concentrations (MICs) of 2 to 4 μM (2.5 to 5.5 μg/mL). The stapled peptides showed increased resistance to enzymatic degradation, particularly with staples incorporated near the N-terminus, and were not haemolytic or cytotoxic at their MICs. Molecular dynamics simulations revealed how stapling aids in (i) stabilising the membrane-active secondary structure of amphipathic peptides and (ii) accelerating their membrane insertion. Our results provide insight into peptide design for antimicrobial use. We show that hydrocarbon stapling of lysine- and leucine-rich short sequences may offer a pathway towards more stable and effective antibacterial agents.
为了应对抗菌药耐药性的挑战，我们研究了基于富含赖氨酸和亮氨酸序列的新型抗菌肽。我们通过在序列的 i 和 i+4 位应用碳氢化合物订书钉来稳定其具有膜活性的二级结构。无论订书钉位置如何，订书钉都能提高肽在水环境和脂质环境中的结构稳定性。它还提高了对革兰氏阴性菌和革兰氏阳性菌（包括抗生素耐药菌株）的抗菌效率，最低抑菌浓度（MIC）为 2 至 4 μM（2.5 至 5.5 μg/mL）。钉合肽显示出更强的抗酶降解能力，尤其是在 N 端附近加入钉合肽时。分子动力学模拟揭示了钉书钉如何（i）稳定两性肽的膜活性二级结构和（ii）加速它们的膜插入。我们的研究结果为抗菌肽的设计提供了启示。我们的研究结果表明，对富含赖氨酸和亮氨酸的短序列进行碳氢化合物钉合处理，可为开发更稳定、更有效的抗菌剂提供一条途径。
{"title":"Design, synthesis and evaluation of lysine- and leucine-rich hydrocarbon-stapled peptides as antibacterial agents","authors":"Małgorzata Lobka, Izabela Siekierska, Piotr Chyży, Michał Burmistrz, Julia Macyszyn, Renata Grzela, Monika Wojciechowska, Joanna Trylska","doi":"10.1016/j.ejmech.2025.117445","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117445","url":null,"abstract":"To address the challenge of antimicrobial resistance, we investigated new antibacterial peptides based on lysine- and leucine-rich sequences. We stabilised their membrane-active secondary structures by applying hydrocarbon stapling at sequence positions <em>i</em> and <em>i</em>+4. Stapling improved peptide structural stability in both aqueous and lipid environments, regardless of the staple position. It also enhanced antibacterial efficiency against both gram-negative and gram-positive bacteria, including antibiotic-resistant strains, with minimum inhibitory concentrations (MICs) of 2 to 4 μM (2.5 to 5.5 μg/mL). The stapled peptides showed increased resistance to enzymatic degradation, particularly with staples incorporated near the N-terminus, and were not haemolytic or cytotoxic at their MICs. Molecular dynamics simulations revealed how stapling aids in (i) stabilising the membrane-active secondary structure of amphipathic peptides and (ii) accelerating their membrane insertion. Our results provide insight into peptide design for antimicrobial use. We show that hydrocarbon stapling of lysine- and leucine-rich short sequences may offer a pathway towards more stable and effective antibacterial agents.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"50 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477674","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 : 2025-02-23DOI: 10.1016/j.ejmech.2025.117430
Syed Azeem Abbas, Hyeon-Min Cha, Sandesha Nayak, Sujin Ahn, Jayaraj Gowda, Ilva Lieknina, Andris Dislers, In Su Kim, Inseong Jo, Meehyein Kim, Hyejin Kim, Chunkyu Ko, Soo Bong Han
Hepatitis B virus (HBV) is a leading cause of chronic hepatitis and remains a significant global public health concern due to the lack of effective treatments. HBV replicates through reverse transcription within the viral capsid, making capsid assembly a promising antiviral target. However, no approved therapies currently target this process. In our previous study, we optimized the structure-activity relationship (SAR) of NVR 3-778 by modifying the A and B rings, leading to the identification of KR-26556 and Compound 3. In this study, we further synthesized derivatives to modify the C ring, resulting in the discovery of KR019 and KR026. These compounds exhibited over 170-fold higher selectivity than the reference compound while demonstrating potent antiviral activity in HBV-replicating cells. Mechanistic studies revealed that KR019 binds to the hydrophobic pocket at the core protein dimer-dimer interface, misdirecting capsid assembly into genome-free capsids and thereby inhibiting viral replication. Additionally, pharmacokinetic profiling confirmed favorable stability and safety. These findings highlight the strong antiviral potential of KR019 and KR026 and provide a foundation for further in vivo investigation.
{"title":"Development of Sulfamoylbenzamide-based Capsid Assembly Modulators for Hepatitis B Virus Capsid Assembly","authors":"Syed Azeem Abbas, Hyeon-Min Cha, Sandesha Nayak, Sujin Ahn, Jayaraj Gowda, Ilva Lieknina, Andris Dislers, In Su Kim, Inseong Jo, Meehyein Kim, Hyejin Kim, Chunkyu Ko, Soo Bong Han","doi":"10.1016/j.ejmech.2025.117430","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117430","url":null,"abstract":"Hepatitis B virus (HBV) is a leading cause of chronic hepatitis and remains a significant global public health concern due to the lack of effective treatments. HBV replicates through reverse transcription within the viral capsid, making capsid assembly a promising antiviral target. However, no approved therapies currently target this process. In our previous study, we optimized the structure-activity relationship (SAR) of <strong>NVR 3</strong>-<strong>778</strong> by modifying the A and B rings, leading to the identification of <strong>KR</strong>-<strong>26556</strong> and <strong>Compound 3</strong>. In this study, we further synthesized derivatives to modify the C ring, resulting in the discovery of <strong>KR019</strong> and <strong>KR026</strong>. These compounds exhibited over 170-fold higher selectivity than the reference compound while demonstrating potent antiviral activity <strong>in HBV-replicating cells</strong>. Mechanistic studies revealed that <strong>KR019</strong> binds to the hydrophobic pocket at the core protein dimer-dimer interface, misdirecting capsid assembly into genome-free capsids and thereby inhibiting viral replication. Additionally, pharmacokinetic profiling confirmed favorable stability and safety. These findings highlight the strong antiviral potential of <strong>KR019</strong> and <strong>KR026</strong> and provide a foundation for further <em>in vivo</em> investigation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"50 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473417","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 : 2025-02-23DOI: 10.1016/j.ejmech.2025.117429
Chaowei Liang, Yongzhi Ma, Minni Ding, Fang Gao, Kewang Yu, Siyu Wang, Ying Qu, Huiming Hua, Dahong Li
Centella asiatica (L.) Urban has been utilized in wound healing remedies for nearly 3000 years. Asiatic acid (AA), a pentacyclic triterpenoid characterized by ursane-type skeleton, serves as principal bioactive constituent of Centella asiatica, exhibits remarkable therapeutic potential across a spectrum of health conditions. Pharmacological investigations have revealed that AA exerts direct regulatory effects on a multitude of enzymes, receptors, inflammatory mediators, and transcription factors. This article systematically examines the therapeutic applications of AA and its derivatives in the management of neurodegenerative diseases, cancer, cardiovascular disorders, and infections. Additionally, recent advancements in the structural modification of AA are summarized, offering new insights for the development of low-toxicity, effective AA-based therapeutics and diagnostic agents. However, several challenges remain, including the paucity of clinical trials, uncertainties in dosage and treatment regimens, limited data on long-term safety and side effects, and poor bioavailability. Addressing these limitations is crucial for advancing AA-based therapies and ensuring their clinical applicability.
{"title":"Asiatic acid and its derivatives: Pharmacological insights and applications","authors":"Chaowei Liang, Yongzhi Ma, Minni Ding, Fang Gao, Kewang Yu, Siyu Wang, Ying Qu, Huiming Hua, Dahong Li","doi":"10.1016/j.ejmech.2025.117429","DOIUrl":"10.1016/j.ejmech.2025.117429","url":null,"abstract":"<div><div><em>Centella asiatica</em> (L.) Urban has been utilized in wound healing remedies for nearly 3000 years. Asiatic acid (<strong>AA</strong>), a pentacyclic triterpenoid characterized by ursane-type skeleton, serves as principal bioactive constituent of <em>Centella asiatica</em>, exhibits remarkable therapeutic potential across a spectrum of health conditions. Pharmacological investigations have revealed that <strong>AA</strong> exerts direct regulatory effects on a multitude of enzymes, receptors, inflammatory mediators, and transcription factors. This article systematically examines the therapeutic applications of <strong>AA</strong> and its derivatives in the management of neurodegenerative diseases, cancer, cardiovascular disorders, and infections. Additionally, recent advancements in the structural modification of <strong>AA</strong> are summarized, offering new insights for the development of low-toxicity, effective <strong>AA</strong>-based therapeutics and diagnostic agents. However, several challenges remain, including the paucity of clinical trials, uncertainties in dosage and treatment regimens, limited data on long-term safety and side effects, and poor bioavailability. Addressing these limitations is crucial for advancing <strong>AA</strong>-based therapies and ensuring their clinical applicability.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117429"},"PeriodicalIF":6.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477675","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 : 2025-02-23DOI: 10.1016/j.ejmech.2025.117438
Ming-Jie Huang , Qiuge Liu , Jian Song , Beiling Gao , Saiyang Zhang , Lihua Huang
As an epigenetic enzyme, Lysine-specific demethylase (LSD1) has emerged as a promising target for cancer therapy. Based on the structure of tranylcypromine indazole, a series of LSD1 inhibitors have been designed and synthesized in this work. Most compounds have excellent inhibitory activity against LSD1. The representative compound, 9e, proved to be a highly effective LSD1 inhibitor, with an IC50 value of 9.85 nM, and demonstrated exceptional selectivity for LSD1 over both MAOs and hERG. Meanwhile, compound 9e exhibited significant inhibitory activity against leukemia cells, especially MV-4-11, HL-60, and THP-1 cells, with IC50 values of 1.40, 1.54, and 1.96 μM respectively. Additional biological mechanisms suggested that compound 9e could directly target LSD1 and inhibit LSD1 in MV-4-11 cells, resulting in a significant increase in the expression levels of H3K4me1/2. In addition, compound 9e was found to induce apoptosis and upregulate of CD86-expression in MV-4-11 cells. All these findings indicated that compound 9e, a tranylcypromine-indazole derivative, provided a structural basis for LSD1 inhibitors in the treatment of acute myeloid leukemia.
{"title":"Discovery of novel tranylcypromine-indazole-based derivatives as LSD1 inhibitors for acute myeloid leukemia treatment","authors":"Ming-Jie Huang , Qiuge Liu , Jian Song , Beiling Gao , Saiyang Zhang , Lihua Huang","doi":"10.1016/j.ejmech.2025.117438","DOIUrl":"10.1016/j.ejmech.2025.117438","url":null,"abstract":"<div><div>As an epigenetic enzyme, Lysine-specific demethylase (LSD1) has emerged as a promising target for cancer therapy. Based on the structure of tranylcypromine indazole, a series of LSD1 inhibitors have been designed and synthesized in this work. Most compounds have excellent inhibitory activity against LSD1. The representative compound, <strong>9e</strong>, proved to be a highly effective LSD1 inhibitor, with an IC<sub>50</sub> value of 9.85 nM, and demonstrated exceptional selectivity for LSD1 over both MAOs and hERG. Meanwhile, compound <strong>9e</strong> exhibited significant inhibitory activity against leukemia cells, especially MV-4-11, HL-60, and THP-1 cells, with IC<sub>50</sub> values of 1.40, 1.54, and 1.96 μM respectively. Additional biological mechanisms suggested that compound <strong>9e</strong> could directly target LSD1 and inhibit LSD1 in MV-4-11 cells, resulting in a significant increase in the expression levels of H3K4me1/2. In addition, compound <strong>9e</strong> was found to induce apoptosis and upregulate of CD86-expression in MV-4-11 cells. All these findings indicated that compound <strong>9e</strong>, a tranylcypromine-indazole derivative, provided a structural basis for LSD1 inhibitors in the treatment of acute myeloid leukemia.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117438"},"PeriodicalIF":6.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473420","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 : 2025-02-23DOI: 10.1016/j.ejmech.2025.117435
Jinxiao Sun, Dezhi Yang , Yongmi Huang, Zhihao Jiao, Shangzhe Yu, Yiru Liu, Kexin Gong, Guisen Zhao
AKT, a serine/threonine protein kinase that plays a pivotal role in the PI3K/AKT/mTOR pathway, is overexpressed or hyperactivated in various cancers, including prostate, breast, and lung cancers. A series of novel nitrogen-containing aromatic heterocyclic compounds were designed, synthesized, and evaluated for AKT inhibition and anticancer activities. Among these, JL16 and JL18 emerged as potent inhibitors of AKT1 kinase, with IC50 values of 7.1 ± 1.2 nM and 8.8 ± 1.3 nM, respectively. Both compounds also demonstrated significant antiproliferative effects against PC-3 prostate cancer cells, with IC50 values of 2.9 ± 0.7 μM (JL16) and 3.0 ± 0.6 μM (JL18). Mechanistic studies revealed that JL16 and JL18 reduced phosphorylated GSK3β levels, confirming AKT target engagement in cells. Notably, JL18 exhibited favorable pharmacokinetic properties in mice, including rapid oral absorption (Tmax = 0.5 h) and 41 % bioavailability. These findings highlight JL16 and JL18 as promising AKT inhibitors for further preclinical development.
{"title":"The discovery of novel N-heterocyclic-based AKT inhibitors with potential efficacy against prostate cancer","authors":"Jinxiao Sun, Dezhi Yang , Yongmi Huang, Zhihao Jiao, Shangzhe Yu, Yiru Liu, Kexin Gong, Guisen Zhao","doi":"10.1016/j.ejmech.2025.117435","DOIUrl":"10.1016/j.ejmech.2025.117435","url":null,"abstract":"<div><div>AKT, a serine/threonine protein kinase that plays a pivotal role in the PI3K/AKT/mTOR pathway, is overexpressed or hyperactivated in various cancers, including prostate, breast, and lung cancers. A series of novel nitrogen-containing aromatic heterocyclic compounds were designed, synthesized, and evaluated for AKT inhibition and anticancer activities. Among these, <strong>JL16</strong> and <strong>JL18</strong> emerged as potent inhibitors of AKT1 kinase, with IC<sub>50</sub> values of 7.1 ± 1.2 nM and 8.8 ± 1.3 nM, respectively. Both compounds also demonstrated significant antiproliferative effects against PC-3 prostate cancer cells, with IC<sub>50</sub> values of 2.9 ± 0.7 μM (<strong>JL16</strong>) and 3.0 ± 0.6 μM (<strong>JL18</strong>). Mechanistic studies revealed that <strong>JL16</strong> and <strong>JL18</strong> reduced phosphorylated GSK3β levels, confirming AKT target engagement in cells. Notably, <strong>JL18</strong> exhibited favorable pharmacokinetic properties in mice, including rapid oral absorption (T<sub>max</sub> = 0.5 h) and 41 % bioavailability. These findings highlight <strong>JL16</strong> and <strong>JL18</strong> as promising AKT inhibitors for further preclinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117435"},"PeriodicalIF":6.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473421","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 : 2025-02-22DOI: 10.1016/j.ejmech.2025.117439
Huan Wang , Zixuan Wang , Xu Zhang , Lipeng Shan , Lei Liu , Yang Hu , Jiong Chen
Rhabdoviruses are diverse pathogens known for their broad host range and significant economic and health impacts. Infectious hematopoietic necrosis virus (IHNV), a member of the Novirhabdovirus genus, poses a major threat to aquaculture, particularly affecting rainbow trout. In this study, we further optimize the antiviral properties of arctigenin derivatives based on our previous structure-activity relationship (SAR) research, leading to the synthesis of TZOA. TZOA was synthesized with a 45 % yield and demonstrated no cytotoxicity up to 25 μM in EPC cells. Treatment with TZOA markedly inhibited IHNV replication dose-dependently, achieving over 90 % suppression of viral N, G, and M genes at 25 μM. Notably, TZOA effectively reduced viral titers compared to controls, demonstrating its potent antiviral activity in vitro. Mechanistically, TZOA preserved mitochondrial integrity, mitigated virus-induced mitochondrial fragmentation, and maintained membrane potential in infected cells. Furthermore, TZOA facilitated mitochondrial fusion and mitophagy, clearing damaged mitochondria, which restored MAVS-mediated interferon expression, thus enhancing the host's innate antiviral response. In vivo studies in juvenile rainbow trout revealed a significant 44 % increase in survival rates with TZOA treatment, accompanied by reduced IHNV-induced mortality and viral gene expression in spleen and kidney tissues. Importantly, TZOA also inhibited IHNV horizontal transmission, highlighting its potential application in controlling viral spread. These findings emphasize TZOA as a promising therapeutic candidate, not only for IHNV but also for broader rhabdovirus infections, offering valuable insights for antiviral drug development in aquaculture and beyond.
{"title":"Arctigenin derivative TZOA restores mitochondrial homeostasis to combat rhabdovirus infections","authors":"Huan Wang , Zixuan Wang , Xu Zhang , Lipeng Shan , Lei Liu , Yang Hu , Jiong Chen","doi":"10.1016/j.ejmech.2025.117439","DOIUrl":"10.1016/j.ejmech.2025.117439","url":null,"abstract":"<div><div>Rhabdoviruses are diverse pathogens known for their broad host range and significant economic and health impacts. Infectious hematopoietic necrosis virus (IHNV), a member of the <em>Novirhabdovirus</em> genus, poses a major threat to aquaculture, particularly affecting rainbow trout. In this study, we further optimize the antiviral properties of arctigenin derivatives based on our previous structure-activity relationship (SAR) research, leading to the synthesis of TZOA. TZOA was synthesized with a 45 % yield and demonstrated no cytotoxicity up to 25 μM in EPC cells. Treatment with TZOA markedly inhibited IHNV replication dose-dependently, achieving over 90 % suppression of viral <em>N</em>, <em>G</em>, and <em>M</em> genes at 25 μM. Notably, TZOA effectively reduced viral titers compared to controls, demonstrating its potent antiviral activity <em>in vitro</em>. Mechanistically, TZOA preserved mitochondrial integrity, mitigated virus-induced mitochondrial fragmentation, and maintained membrane potential in infected cells. Furthermore, TZOA facilitated mitochondrial fusion and mitophagy, clearing damaged mitochondria, which restored MAVS-mediated interferon expression, thus enhancing the host's innate antiviral response. <em>In vivo</em> studies in juvenile rainbow trout revealed a significant 44 % increase in survival rates with TZOA treatment, accompanied by reduced IHNV-induced mortality and viral gene expression in spleen and kidney tissues. Importantly, TZOA also inhibited IHNV horizontal transmission, highlighting its potential application in controlling viral spread. These findings emphasize TZOA as a promising therapeutic candidate, not only for IHNV but also for broader rhabdovirus infections, offering valuable insights for antiviral drug development in aquaculture and beyond.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117439"},"PeriodicalIF":6.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473422","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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