Pub Date : 2025-11-13DOI: 10.1016/j.ejmech.2025.118372
Yinglong Li, Yanyun Hong, Jianye Zhang, Shan Xu
As a paracaspase, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) plays a crucial role in the NF-κB signaling pathway. It typically exerts its function by forming a ternary complex with CARMA and BCL. The structure of MALT1 endows it with dual roles as a protease and a scaffold protein, both of which are of great significance for the regulation of the signaling pathway. Activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) is characterized by high complication rates and mortality. Studies have demonstrated that its pathogenesis relies on the NF-κB pathway mediated by the CBM complex (CARMA-Bcl10-MALT1 complex). As the only human cysteine-aspartic acid protease (caspase-like protease) in the CBM complex, MALT1 has thus become a key target, making the research on MALT1 inhibitors of substantial importance. This review provides an overview of the research progress and structure-activity relationships (SARs) of MALT1 inhibitors, including covalent inhibitors, allosteric inhibitors, PROTACs (Proteolysis-Targeting Chimeras), and activity-based probes. Additionally, it discusses the future opportunities and challenges in this field, aiming to provide insights for the future development of MALT1-targeted drugs.
{"title":"Targeting paracaspase1 (MALT1) for cancer therapy: Updated progress and study on structure-activity relationships (SARs)","authors":"Yinglong Li, Yanyun Hong, Jianye Zhang, Shan Xu","doi":"10.1016/j.ejmech.2025.118372","DOIUrl":"10.1016/j.ejmech.2025.118372","url":null,"abstract":"<div><div>As a paracaspase, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) plays a crucial role in the NF-κB signaling pathway. It typically exerts its function by forming a ternary complex with CARMA and BCL. The structure of MALT1 endows it with dual roles as a protease and a scaffold protein, both of which are of great significance for the regulation of the signaling pathway. Activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) is characterized by high complication rates and mortality. Studies have demonstrated that its pathogenesis relies on the NF-κB pathway mediated by the CBM complex (CARMA-Bcl10-MALT1 complex). As the only human cysteine-aspartic acid protease (caspase-like protease) in the CBM complex, MALT1 has thus become a key target, making the research on MALT1 inhibitors of substantial importance. This review provides an overview of the research progress and structure-activity relationships (SARs) of MALT1 inhibitors, including covalent inhibitors, allosteric inhibitors, PROTACs (Proteolysis-Targeting Chimeras), and activity-based probes. Additionally, it discusses the future opportunities and challenges in this field, aiming to provide insights for the future development of MALT1-targeted drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118372"},"PeriodicalIF":5.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509048","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 : 2025-11-13DOI: 10.1016/j.ejmech.2025.118348
Mustafa A. Al-Qadhi , Tawfeek A.A. Yahya , Anas A. Alqadhi , Reem K. Arafa
The pyrazolo[1,5-a]pyrimidine scaffold has emerged as a privileged structure in medicinal chemistry, particularly in designing kinase-targeted therapeutics, such as tropomyosin receptor kinase (TRK) inhibitors, for targeted cancer therapy. This review provides a critical analysis of small molecules bearing this heterocyclic motif, focusing on their chemical evolution, structure-activity relationship (SAR)- driven optimization, mechanistic insights into TRK inhibition, and the translational journey of these compounds from preclinical studies to FDA-approved drugs, such as Larotrectinib. The review highlights the strategic chemical modifications that improved selectivity, pharmacokinetics, and safety profiles of TRK inhibitors. Additionally, it outlines the evolution of kinase inhibitor design strategies leveraging this scaffold and discusses current challenges and future directions in optimizing these compounds for broader clinical applications. This work aims to serve as a foundation for ongoing drug discovery efforts utilizing the pyrazolo[1,5-a]pyrimidine core in oncogenic kinase targeting. Collectively, this work underscores the significance of the pyrazolo[1,5-a]pyrimidine scaffold as a privileged chemotype and sets the stage for the rational development of next-generation TRK inhibitors with enhanced clinical utility.
{"title":"Pyrazolo[1,5-a]pyrimidine scaffold-based small molecules: From bench to FDA-approved TRK kinase inhibitors (Part 1)","authors":"Mustafa A. Al-Qadhi , Tawfeek A.A. Yahya , Anas A. Alqadhi , Reem K. Arafa","doi":"10.1016/j.ejmech.2025.118348","DOIUrl":"10.1016/j.ejmech.2025.118348","url":null,"abstract":"<div><div>The pyrazolo[1,5-a]pyrimidine scaffold has emerged as a privileged structure in medicinal chemistry, particularly in designing kinase-targeted therapeutics, such as tropomyosin receptor kinase (TRK) inhibitors, for targeted cancer therapy. This review provides a critical analysis of small molecules bearing this heterocyclic motif, focusing on their chemical evolution, structure-activity relationship (SAR)- driven optimization, mechanistic insights into TRK inhibition, and the translational journey of these compounds from preclinical studies to FDA-approved drugs, such as Larotrectinib. The review highlights the strategic chemical modifications that improved selectivity, pharmacokinetics, and safety profiles of TRK inhibitors. Additionally, it outlines the evolution of kinase inhibitor design strategies leveraging this scaffold and discusses current challenges and future directions in optimizing these compounds for broader clinical applications. This work aims to serve as a foundation for ongoing drug discovery efforts utilizing the pyrazolo[1,5-a]pyrimidine core in oncogenic kinase targeting. Collectively, this work underscores the significance of the pyrazolo[1,5-a]pyrimidine scaffold as a privileged chemotype and sets the stage for the rational development of next-generation TRK inhibitors with enhanced clinical utility.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118348"},"PeriodicalIF":5.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498837","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 : 2025-11-12DOI: 10.1016/j.ejmech.2025.118371
Umam Khan , Moazzam Ahmad , Mariam Tuba , Raabia Naaz , Fayeqa Qayum , Shahnaaz Khatoon , Sanobar , Shakir Ahamad , Mohammad Saquib , Mohd Kamil Hussain
Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which the decline of cholinergic neurotransmission plays a central role in cognitive impairment. Cholinesterase inhibition remains an established therapeutic approach to enhance acetylcholine levels and provide symptomatic relief. Natural alkaloids have long served as an important source of cholinesterase inhibitors, offering diverse molecular scaffolds, stereochemical complexity, and strong biological relevance. This review provides a comprehensive overview of natural alkaloids reported as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, highlighting their structural diversity, mechanisms of inhibition, and structure–activity relationships. In addition, the review presents a brief analysis on the emerging pseudo-natural product (PNP) framework as a complementary strategy for designing new alkaloid-inspired potential inhibitors that combine nature-derived functionality with synthetic innovation. Overall, the manuscript underscores the enduring significance of alkaloids in cholinesterase inhibitor discovery and their potential in developing next-generation therapeutics for AD.
{"title":"Natural alkaloids with therapeutic potential against Alzheimer's disease through cholinesterase inhibition","authors":"Umam Khan , Moazzam Ahmad , Mariam Tuba , Raabia Naaz , Fayeqa Qayum , Shahnaaz Khatoon , Sanobar , Shakir Ahamad , Mohammad Saquib , Mohd Kamil Hussain","doi":"10.1016/j.ejmech.2025.118371","DOIUrl":"10.1016/j.ejmech.2025.118371","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which the decline of cholinergic neurotransmission plays a central role in cognitive impairment. Cholinesterase inhibition remains an established therapeutic approach to enhance acetylcholine levels and provide symptomatic relief. Natural alkaloids have long served as an important source of cholinesterase inhibitors, offering diverse molecular scaffolds, stereochemical complexity, and strong biological relevance. This review provides a comprehensive overview of natural alkaloids reported as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, highlighting their structural diversity, mechanisms of inhibition, and structure–activity relationships. In addition, the review presents a brief analysis on the emerging pseudo-natural product (PNP) framework as a complementary strategy for designing new alkaloid-inspired potential inhibitors that combine nature-derived functionality with synthetic innovation. Overall, the manuscript underscores the enduring significance of alkaloids in cholinesterase inhibitor discovery and their potential in developing next-generation therapeutics for AD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118371"},"PeriodicalIF":5.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498228","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 : 2025-11-12DOI: 10.1016/j.ejmech.2025.118358
Hossam Nada , Shaoren Yuan , Farida El Gaamouch , Sungwoo Cho , Katarzyna Kuncewicz , Laura Calvo-Barreiro , Moustafa T. Gabr
Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function, and its loss-of-function variants are linked to Alzheimer's disease (AD) and neurodegenerative disorders. While TREM2 activation is a promising therapeutic strategy, no small molecule agonists acting via direct TREM2 binding have been reported to date. Here, we describe the discovery of first-in-class, direct small molecule TREM2 agonists identified through DNA-encoded library (DEL) screening. The DEL hit (4a) demonstrated TREM2 binding affinity, as validated by three biophysical screening platforms (TRIC, MST, and SPR), induced Syk phosphorylation, luciferase assay and enhanced microglial phagocytosis. Pre-liminary optimization yielded 4i, which maintained TREM2 engagement with improved selectivity over TREM1 and no cytotoxicity. Molecular dynamics simulations predicted that 4a stabilizes a transient binding pocket on TREM2, indicating the possibility of a novel mechanism for receptor activation. These findings provide the first proof-of-concept for direct pharmacological TREM2 agonism, offering a foundation for developing therapeutics against AD and related disorders.
髓样细胞上表达的触发受体2 （TREM2）是小胶质细胞功能的关键调节因子，其功能丧失变体与阿尔茨海默病（AD）和神经退行性疾病有关。虽然激活TREM2是一种很有前景的治疗策略，但迄今为止还没有报道过通过直接结合TREM2起作用的小分子激动剂。在这里，我们描述了通过dna编码文库（DEL）筛选鉴定的一流的直接小分子TREM2激动剂的发现。通过三种生物物理筛选平台（TRIC、MST和SPR）验证，DEL hit （4a）显示出TREM2结合亲和力，诱导Syk磷酸化、荧光素酶测定和增强小胶质细胞吞噬。初步优化得到了4i，它保持了TREM2的结合，比TREM1具有更高的选择性，并且没有细胞毒性。分子动力学模拟预测4a稳定了TREM2上的瞬时结合袋，这表明可能存在一种新的受体激活机制。这些发现首次提供了直接药理TREM2激动作用的概念证明，为开发针对AD和相关疾病的治疗方法提供了基础。
{"title":"TREM2 activation by first-in-class direct small molecule agonists: DEL screening, optimization, biophysical validation, and functional characterization","authors":"Hossam Nada , Shaoren Yuan , Farida El Gaamouch , Sungwoo Cho , Katarzyna Kuncewicz , Laura Calvo-Barreiro , Moustafa T. Gabr","doi":"10.1016/j.ejmech.2025.118358","DOIUrl":"10.1016/j.ejmech.2025.118358","url":null,"abstract":"<div><div>Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function, and its loss-of-function variants are linked to Alzheimer's disease (AD) and neurodegenerative disorders. While TREM2 activation is a promising therapeutic strategy, no small molecule agonists acting via direct TREM2 binding have been reported to date. Here, we describe the discovery of first-in-class, direct small molecule TREM2 agonists identified through DNA-encoded library (DEL) screening. The DEL hit (4a) demonstrated TREM2 binding affinity, as validated by three biophysical screening platforms (TRIC, MST, and SPR), induced Syk phosphorylation, luciferase assay and enhanced microglial phagocytosis. Pre-liminary optimization yielded 4i, which maintained TREM2 engagement with improved selectivity over TREM1 and no cytotoxicity. Molecular dynamics simulations predicted that 4a stabilizes a transient binding pocket on TREM2, indicating the possibility of a novel mechanism for receptor activation. These findings provide the first proof-of-concept for direct pharmacological TREM2 agonism, offering a foundation for developing therapeutics against AD and related disorders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118358"},"PeriodicalIF":5.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498833","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 : 2025-11-12DOI: 10.1016/j.ejmech.2025.118354
Jian-Tao Shi , Su-Juan Hou , Cheng-Long Xu , Lei Cheng , Feng-Ya Ge , Xiu-Juan Liu , Yi-Ru Wang , Xi-Bo Wang , Yao-Sheng Zhang , Junmin Zhang , Shi-Wu Chen
KRAS-G12C is a validated therapeutic target for KRAS-mutant cancers. However, current KRAS-G12C inhibitors face limitations due to structural homogeneity and the emergence of drug resistance. To address this, we employed virtual screening to identify novel pyrimidine-based KRAS-G12C inhibitors, followed by rational structural optimization. Among the optimized compounds, KD36 significantly inhibited the proliferation of KRAS-G12C mutant NSCLC cell lines (NCI–H23 and NCI–H358) in a dose-dependent manner. Mechanistically, KD36 suppressed the phosphorylation of KRAS downstream effectors ERK and AKT. Importantly, KD36 induced intrinsic (mitochondrial) apoptosis in NCI–H23 cells. Critically, in an NCI–H358 xenograft mouse model, KD36 (at 30 mg/kg) exhibited significant tumor growth inhibition with 54.6 % tumor growth inhibition (TGI), without apparent systemic toxicity. These findings establish KD36 as a promising, structurally novel pyrimidine-based KRAS-G12C inhibitor lead compound with potent anti-tumor efficacy against KRAS-G12C mutant NSCLC, demonstrating the success of our virtual screening and optimization strategy in overcoming scaffold limitations.
{"title":"Discovery of novel pyrimidine-based KRAS-G12C inhibitors with potent anti-NSCLC activity via virtual screening and structure optimization","authors":"Jian-Tao Shi , Su-Juan Hou , Cheng-Long Xu , Lei Cheng , Feng-Ya Ge , Xiu-Juan Liu , Yi-Ru Wang , Xi-Bo Wang , Yao-Sheng Zhang , Junmin Zhang , Shi-Wu Chen","doi":"10.1016/j.ejmech.2025.118354","DOIUrl":"10.1016/j.ejmech.2025.118354","url":null,"abstract":"<div><div>KRAS-G12C is a validated therapeutic target for KRAS-mutant cancers. However, current KRAS-G12C inhibitors face limitations due to structural homogeneity and the emergence of drug resistance. To address this, we employed virtual screening to identify novel pyrimidine-based KRAS-G12C inhibitors, followed by rational structural optimization. Among the optimized compounds, <strong>KD36</strong> significantly inhibited the proliferation of KRAS-G12C mutant NSCLC cell lines (NCI–H23 and NCI–H358) in a dose-dependent manner. Mechanistically, <strong>KD36</strong> suppressed the phosphorylation of KRAS downstream effectors ERK and AKT. Importantly, <strong>KD36</strong> induced intrinsic (mitochondrial) apoptosis in NCI–H23 cells. Critically, in an NCI–H358 xenograft mouse model, <strong>KD36</strong> (at 30 mg/kg) exhibited significant tumor growth inhibition with 54.6 % tumor growth inhibition (TGI), without apparent systemic toxicity. These findings establish <strong>KD36</strong> as a promising, structurally novel pyrimidine-based KRAS-G12C inhibitor lead compound with potent anti-tumor efficacy against KRAS-G12C mutant NSCLC, demonstrating the success of our virtual screening and optimization strategy in overcoming scaffold limitations.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118354"},"PeriodicalIF":5.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498841","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}
As bacterial infections caused by antibiotic-resistant strains become increasingly prevalent, traditional antibacterial therapies face mounting challenges. These resilient pathogens not only complicate the treatment of common infections but also undermine the efficacy of therapies for major diseases. This growing threat underscores the urgent need for innovative therapeutic strategies. In recent years, the combinatorial use of antibacterial agents has emerged as a promising approach to enhance efficacy and combat resistant bacteria. This review first provides an overview of antibacterial classifications and their mechanisms of action against bacterial infections. It then explores two combined treatment strategies: antibacterial–antibacterial combinations and antibacterial–non-antibacterial pairings, alongside a drug delivery technology: antibacterial-loaded liposomes. Furthermore, we highlight emerging frontiers in antimicrobial strategies, including CRISPR-Cas technologies, AI-driven discovery platforms, nanomaterials beyond liposomes, microbiota-based therapies, and immunotherapeutic approaches. Finally, we offer a forward-looking perspective on the challenges and opportunities shaping the future of antibacterial development in the biomedical field.
{"title":"Beyond traditional antibacterial agents: Novel approaches to combat resistant pathogens","authors":"Wei Zong , Shengjie Xie , Hongtao Chu , Shuang Han , Xunan Zhang","doi":"10.1016/j.ejmech.2025.118362","DOIUrl":"10.1016/j.ejmech.2025.118362","url":null,"abstract":"<div><div>As bacterial infections caused by antibiotic-resistant strains become increasingly prevalent, traditional antibacterial therapies face mounting challenges. These resilient pathogens not only complicate the treatment of common infections but also undermine the efficacy of therapies for major diseases. This growing threat underscores the urgent need for innovative therapeutic strategies. In recent years, the combinatorial use of antibacterial agents has emerged as a promising approach to enhance efficacy and combat resistant bacteria. This review first provides an overview of antibacterial classifications and their mechanisms of action against bacterial infections. It then explores two combined treatment strategies: antibacterial–antibacterial combinations and antibacterial–non-antibacterial pairings, alongside a drug delivery technology: antibacterial-loaded liposomes. Furthermore, we highlight emerging frontiers in antimicrobial strategies, including CRISPR-Cas technologies, AI-driven discovery platforms, nanomaterials beyond liposomes, microbiota-based therapies, and immunotherapeutic approaches. Finally, we offer a forward-looking perspective on the challenges and opportunities shaping the future of antibacterial development in the biomedical field.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118362"},"PeriodicalIF":5.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485399","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 : 2025-11-10DOI: 10.1016/j.ejmech.2025.118359
Landry Anamea , Adéla Králová , Janne Tampio , Anastasia Shakirzyanova , Milka Hänninen , Rashid Giniatullin , Aaro J. Jalkanen , Tarja Malm , Kristiina M. Huttunen
Mechanosensitive Piezo1 channel is highly expressed in the eukaryotic central nervous system and involved in many important physiological functions that maintain cell homeostasis. This membrane ion channel is opened by different forms of mechanical and chemical stimulation. However, pharmacological tools for Piezo1 channel manipulations and in vivo application are limited. In the present study, to address this need, 12 L-type amino acid transporter 1 (LAT1)-utilizing brain-targeted conjugates of Piezo1 activators, Jedi1 and Jedi2, were synthesized and evaluated for their physicochemical and pharmaceutical properties. As a result, the novel compounds were more effectively transported via LAT1 into mouse BV2 microglia cells. Moreover, compared to their parent compounds, they had a higher ability to activate Piezo1 measured by a fluorescent live calcium imaging assay. Furthermore, the pharmacokinetic study revealed that the compounds were delivered into the mouse brain and were distributed to other peripheral tissues to a lesser extent than their parent compound, Jedi2. Therefore, these novel conjugates can be considered as potential compounds to achieve brain- and microglia-targeted delivery and potential neuroprotective effects via Piezo1 ion channel activation, being beneficial in the treatment of neurodegenerative disorders.
{"title":"Brain-targeted Jedi1 and Jedi2 derivatives as potent enhancers of Piezo1 ion channel activity","authors":"Landry Anamea , Adéla Králová , Janne Tampio , Anastasia Shakirzyanova , Milka Hänninen , Rashid Giniatullin , Aaro J. Jalkanen , Tarja Malm , Kristiina M. Huttunen","doi":"10.1016/j.ejmech.2025.118359","DOIUrl":"10.1016/j.ejmech.2025.118359","url":null,"abstract":"<div><div>Mechanosensitive Piezo1 channel is highly expressed in the eukaryotic central nervous system and involved in many important physiological functions that maintain cell homeostasis. This membrane ion channel is opened by different forms of mechanical and chemical stimulation. However, pharmacological tools for Piezo1 channel manipulations and <em>in vivo</em> application are limited. In the present study, to address this need, 12 L-type amino acid transporter 1 (LAT1)-utilizing brain-targeted conjugates of Piezo1 activators, Jedi1 and Jedi2, were synthesized and evaluated for their physicochemical and pharmaceutical properties. As a result, the novel compounds were more effectively transported via LAT1 into mouse BV2 microglia cells. Moreover, compared to their parent compounds, they had a higher ability to activate Piezo1 measured by a fluorescent live calcium imaging assay. Furthermore, the pharmacokinetic study revealed that the compounds were delivered into the mouse brain and were distributed to other peripheral tissues to a lesser extent than their parent compound, Jedi2. Therefore, these novel conjugates can be considered as potential compounds to achieve brain- and microglia-targeted delivery and potential neuroprotective effects via Piezo1 ion channel activation, being beneficial in the treatment of neurodegenerative disorders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118359"},"PeriodicalIF":5.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485278","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 : 2025-11-10DOI: 10.1016/j.ejmech.2025.118360
Nika Strašek Benedik , David Lukić , Tjaša Slokan , Ana Dolšak , Urban Švajger , Simona Kranjc Brezar , Valerij Talagayev , Gerhard Wolber , Maja Čemažar , Izidor Sosič , Matej Sova
Toll-like receptors (TLRs) 7 and 8 are intracellular pattern recognition receptors that play a crucial role in the innate immune system, making them promising targets for the treatment of viral infections, autoimmune diseases and cancer. In this study, we present the synthesis and biological evaluation of quinazolin-4(3H)-one derivatives as a new class of dual TLR7/8 agonists. In a comprehensive structure-activity relationship (SAR) study, different substitutions on the quinazoline ring and modifications of the aliphatic side chain were investigated. Several compounds showed significantly improved potency compared to the original hit compound, with EC50 values in the nanomolar and low micromolar range for TLR7 and TLR8, respectively. The most potent compounds significantly increased the secretion of the proinflammatory cytokines TNF-α, IL-1β, IL-8 and interferon γ in peripheral blood mononuclear cells (PBMCs). In addition, increased secretion of TNF-α and upregulated CD86 expression in dendritic cells were also observed, indicating their immunomodulatory properties. Notably, the most potent compound 69 significantly suppressed tumor growth in vivo in the CT26 mouse tumor model after intratumoral administration. These results highlight the potential of quinazolinone-based compounds as promising candidates for further development of new immunomodulatory agents targeting TLR7 and TLR8.
{"title":"Synthesis and structure-activity relationship study of novel quinazolin-4(3H)-one derivatives as Toll-like receptor 7 and 8 agonists with immunomodulatory activity","authors":"Nika Strašek Benedik , David Lukić , Tjaša Slokan , Ana Dolšak , Urban Švajger , Simona Kranjc Brezar , Valerij Talagayev , Gerhard Wolber , Maja Čemažar , Izidor Sosič , Matej Sova","doi":"10.1016/j.ejmech.2025.118360","DOIUrl":"10.1016/j.ejmech.2025.118360","url":null,"abstract":"<div><div>Toll-like receptors (TLRs) 7 and 8 are intracellular pattern recognition receptors that play a crucial role in the innate immune system, making them promising targets for the treatment of viral infections, autoimmune diseases and cancer. In this study, we present the synthesis and biological evaluation of quinazolin-4(3<em>H</em>)-one derivatives as a new class of dual TLR7/8 agonists. In a comprehensive structure-activity relationship (SAR) study, different substitutions on the quinazoline ring and modifications of the aliphatic side chain were investigated. Several compounds showed significantly improved potency compared to the original hit compound, with EC<sub>50</sub> values in the nanomolar and low micromolar range for TLR7 and TLR8, respectively. The most potent compounds significantly increased the secretion of the proinflammatory cytokines TNF-α, IL-1β, IL-8 and interferon γ in peripheral blood mononuclear cells (PBMCs). In addition, increased secretion of TNF-α and upregulated CD86 expression in dendritic cells were also observed, indicating their immunomodulatory properties. Notably, the most potent compound <strong>69</strong> significantly suppressed tumor growth <em>in vivo</em> in the CT26 mouse tumor model after intratumoral administration. These results highlight the potential of quinazolinone-based compounds as promising candidates for further development of new immunomodulatory agents targeting TLR7 and TLR8.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118360"},"PeriodicalIF":5.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145478019","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 : 2025-11-08DOI: 10.1016/j.ejmech.2025.118355
Jian Xue , Meng Li , Ying Wang , Donghui Sun , Shilong Hao , Zhuochao Liu , Weibin Zhang , Lei Li , Tong Zhu , Shunying Liu
Osteosarcoma (OS) is a rare malignant tumor and has the second-highest mortality rate of malignant tumors in children. Due to its unclear pathogenesis and therapeutic targets, there has been no significant progress in the targeted therapy of OS in the past 50 years. Therefore, it is critically important to develop new drug targets for OS. In this study, a covalent molecule library consisting of 61 small molecules was constructed based on our previous research. Phenotypic screening revealed that small molecule 8e effectively inhibited the proliferation of OS 143B cells, with an IC50 value of 0.73 μM. Compound 8e also showed good antitumor effects and low toxicity in a xenograft model (30.1 % inhibition of OS growth in BALB/c nude mice). Using compound 9a as an efficient activity-based protein profiling (ABPP) probe, eukaryotic protein elongation factor 1 alpha 2 (EEF1A2) was then enriched and conveniently identified as a potential target. The potential target was validated by pull-down assay, cellular thermal shift assay (CETSA), mass spectrometry analysis, molecular docking, and in vitro and in vivo functional studies. Mechanistic studies suggest that compound 8e-induced 143B cell apoptotic is mediated by EEF1A2 inhibition of the AKT signaling pathway and EEF1A2 serves as a potential candidate for targeted OS therapy.
{"title":"Identification of EEF1A2 as a potential therapy target of osteosarcoma using novel compound 8e","authors":"Jian Xue , Meng Li , Ying Wang , Donghui Sun , Shilong Hao , Zhuochao Liu , Weibin Zhang , Lei Li , Tong Zhu , Shunying Liu","doi":"10.1016/j.ejmech.2025.118355","DOIUrl":"10.1016/j.ejmech.2025.118355","url":null,"abstract":"<div><div>Osteosarcoma (OS) is a rare malignant tumor and has the second-highest mortality rate of malignant tumors in children. Due to its unclear pathogenesis and therapeutic targets, there has been no significant progress in the targeted therapy of OS in the past 50 years. Therefore, it is critically important to develop new drug targets for OS. In this study, a covalent molecule library consisting of 61 small molecules was constructed based on our previous research. Phenotypic screening revealed that small molecule <strong>8e</strong> effectively inhibited the proliferation of OS 143B cells, with an IC<sub>50</sub> value of 0.73 μM. Compound <strong>8e</strong> also showed good antitumor effects and low toxicity in a xenograft model (30.1 % inhibition of OS growth in BALB/c nude mice). Using compound <strong>9a</strong> as an efficient activity-based protein profiling (ABPP) probe, eukaryotic protein elongation factor 1 alpha 2 (EEF1A2) was then enriched and conveniently identified as a potential target. The potential target was validated by pull-down assay, cellular thermal shift assay (CETSA), mass spectrometry analysis, molecular docking, and in vitro and in vivo functional studies. Mechanistic studies suggest that compound <strong>8e</strong>-induced 143B cell apoptotic is mediated by EEF1A2 inhibition of the AKT signaling pathway and EEF1A2 serves as a potential candidate for targeted OS therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118355"},"PeriodicalIF":5.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462276","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 : 2025-11-08DOI: 10.1016/j.ejmech.2025.118356
Binbin Cheng , Chao Li , Xixiang Yang , Yinrong Wu , Yong Ruan , Yichang Ren , Zhenhong Su , Shanhe Wan , Xin Li , Dulin Kong , Jianjun Chen
Building on our previous research, a series of novel imidazo[1,2-a]pyridine derivatives were rationally designed and synthesized as tubulin polymerization inhibitors. Among these analogues, compound 5b exhibited the strongest antiproliferative activity against Jurkat, B16–F10, HCT116, and MDA-MB-231 cells, with IC50 values of 60 nM, 380 nM, 138 nM, and 1.054 μM, respectively. Further functional assays revealed that 5b can effectively suppress the migration and colony-forming capacity of B16–F10 cells. Mechanistically, compound 5b induced apoptosis and arrested the cell cycle in the G2/M phase by inhibiting tubulin polymerization. Molecular docking simulations revealed that 5b efficiently binds to the colchicine-binding pocket of tubulin, providing a structural basis for its activity. In vivo, compound 5b (10 mg/kg) demonstrated potent anti-tumor efficacy in a melanoma model without obvious systemic toxicity. Notably, 5b markedly potentiated the in vivo anti-tumor immune response through its combination with a PD-L1 monoclonal antibody (mAb), as evidenced by increased infiltration of cytotoxic CD8+ effector T cells in tumor tissues. Collectively, these findings identify 5b as a promising tubulin polymerization inhibitor with immune-modulatory potential, meriting further investigation.
{"title":"Novel imidazo[1,2-a]pyridine-based tubulin polymerization inhibitors: Structure-activity relationships and anti-tumor immune potentiation","authors":"Binbin Cheng , Chao Li , Xixiang Yang , Yinrong Wu , Yong Ruan , Yichang Ren , Zhenhong Su , Shanhe Wan , Xin Li , Dulin Kong , Jianjun Chen","doi":"10.1016/j.ejmech.2025.118356","DOIUrl":"10.1016/j.ejmech.2025.118356","url":null,"abstract":"<div><div>Building on our previous research, a series of novel imidazo[1,2-<em>a</em>]pyridine derivatives were rationally designed and synthesized as tubulin polymerization inhibitors. Among these analogues, compound <strong>5b</strong> exhibited the strongest antiproliferative activity against Jurkat, B16–F10, HCT116, and MDA-MB-231 cells, with IC<sub>50</sub> values of 60 nM, 380 nM, 138 nM, and 1.054 μM, respectively. Further functional assays revealed that <strong>5b</strong> can effectively suppress the migration and colony-forming capacity of B16–F10 cells. Mechanistically, compound <strong>5b</strong> induced apoptosis and arrested the cell cycle in the G2/M phase by inhibiting tubulin polymerization. Molecular docking simulations revealed that <strong>5b</strong> efficiently binds to the colchicine-binding pocket of tubulin, providing a structural basis for its activity. <em>In vivo</em>, compound <strong>5b</strong> (10 mg/kg) demonstrated potent anti-tumor efficacy in a melanoma model without obvious systemic toxicity. Notably, <strong>5b</strong> markedly potentiated the <em>in vivo</em> anti-tumor immune response through its combination with a PD-L1 monoclonal antibody (mAb), as evidenced by increased infiltration of cytotoxic CD8<sup>+</sup> effector T cells in tumor tissues. Collectively, these findings identify <strong>5b</strong> as a promising tubulin polymerization inhibitor with immune-modulatory potential, meriting further investigation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118356"},"PeriodicalIF":5.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462275","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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