Pub Date : 2025-12-15DOI: 10.1016/j.ejmech.2025.118496
Huiqiong Li, Qiuju Xun, Bowen Yang, Yuan Tian, Pinglian Wu, Shaohua Chang, Xiaomei Ren, Zhen Wang, Ke Ding, Dawei Ma
Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 inhibitor 7. The structures and purity of all target compounds were confirmed by 1H NMR, 13C NMR, HRMS and HPLC analyses. Compound LHQ766 exhibited strong enzymatic inhibition (IC50 = 7.3 nM against FGFR2), good kinase selectivity (selective over FGFR1/3/4 and 72 other tyrosine kinases), and remarkable cellular potency (IC50 = 0.5 nM in BaF3-FGFR2 cells). Mechanistic studies through computational modeling and mass spectrometry revealed LHQ766's covalent binding mode with FGFR2. The compound demonstrated dose-dependent suppression of FGFR2 signaling pathways and selective anti-proliferative effects in FGFR2-driven cancer models. As a key advancement over lead compound 7, LHQ766 showed substantially optimized pharmacokinetic properties, achieving 35.9% oral bioavailability in rats. These findings positioned LHQ766 as a promising lead compound for targeted FGFR2 therapy.
{"title":"Synthesis and Optimization of LHQ766: A Highly Selective FGFR2 Inhibitor with Improved Pharmacokinetics","authors":"Huiqiong Li, Qiuju Xun, Bowen Yang, Yuan Tian, Pinglian Wu, Shaohua Chang, Xiaomei Ren, Zhen Wang, Ke Ding, Dawei Ma","doi":"10.1016/j.ejmech.2025.118496","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118496","url":null,"abstract":"Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present <strong>LHQ766</strong>, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 inhibitor <strong>7</strong>. The structures and purity of all target compounds were confirmed by <sup>1</sup>H NMR, <sup>13</sup>C NMR, HRMS and HPLC analyses. Compound <strong>LHQ766</strong> exhibited strong enzymatic inhibition (IC<sub>50</sub> = 7.3 nM against FGFR2), good kinase selectivity (selective over FGFR1/3/4 and 72 other tyrosine kinases), and remarkable cellular potency (IC<sub>50</sub> = 0.5 nM in BaF3-FGFR2 cells). Mechanistic studies through computational modeling and mass spectrometry revealed <strong>LHQ766</strong>'s covalent binding mode with FGFR2. The compound demonstrated dose-dependent suppression of FGFR2 signaling pathways and selective anti-proliferative effects in FGFR2-driven cancer models. As a key advancement over lead compound <strong>7</strong>, <strong>LHQ766</strong> showed substantially optimized pharmacokinetic properties, achieving 35.9% oral bioavailability in rats. These findings positioned <strong>LHQ766</strong> as a promising lead compound for targeted FGFR2 therapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760231","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 : 2025-12-13DOI: 10.1016/j.ejmech.2025.118484
Amel Djehal, Mohammad Krayem, Ahmad Najem, Hassan Hammoud, Thierry Cresteil, Canan G. Nebigil, Dong Wang, Peng Yu, Embarek Bentouhami, Ghanem E. Ghanem, Laurent Désaubry
{"title":"Corrigendum to “Targeting prohibitin with small molecules unravels a common signaling pathway for melanogenesis and apoptosis in melanoma cells” [Eur. J. Med. Chem. 155 (2018) 880]","authors":"Amel Djehal, Mohammad Krayem, Ahmad Najem, Hassan Hammoud, Thierry Cresteil, Canan G. Nebigil, Dong Wang, Peng Yu, Embarek Bentouhami, Ghanem E. Ghanem, Laurent Désaubry","doi":"10.1016/j.ejmech.2025.118484","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118484","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731738","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 : 2025-12-13DOI: 10.1016/j.ejmech.2025.118485
Hwangeui Cho, Sumi Lee
The Keap1-Nrf2 signaling pathway is recognized as a central regulator of cellular protection against oxidative and electrophilic stress, and its pharmacological modulation has attracted considerable attention in drug discovery. Disruption of the Keap1-Nrf2 protein-protein interaction (PPI) has been proposed as an effective strategy to stabilize and activate Nrf2, thereby enhancing the expression of cytoprotective genes. In this review, we provide a comprehensive overview of recent progress in developing direct small-molecule Keap1-Nrf2 PPI inhibitors, spanning diverse chemotypes such as tetrahydroisoquinoline, 1,4-diaminonaphthalene, and other privileged scaffolds. We further summarize advances in Keap1-based PROTACs, one class of which employs targeted Keap1 degradation as an alternative strategy to achieve sustained Nrf2 activation. Special emphasis is placed on the evolution of structure-activity relationships (SAR), optimization of drug-like properties, and validation of pharmacological efficacy in preclinical models, covering disorders such as acute renal and hepatic injury, chronic lung disorders, neurodegeneration, and metabolic dysfunction. Together, these findings underscore the translational potential of Nrf2 activators in various disease contexts and highlight Keap1 as an attractive therapeutic target for future medicinal chemistry efforts.
{"title":"Direct small-molecule inhibitors of the Keap1-Nrf2 protein-protein interaction: Scaffold evolution, PROTAC strategies, and therapeutic implications","authors":"Hwangeui Cho, Sumi Lee","doi":"10.1016/j.ejmech.2025.118485","DOIUrl":"10.1016/j.ejmech.2025.118485","url":null,"abstract":"<div><div>The Keap1-Nrf2 signaling pathway is recognized as a central regulator of cellular protection against oxidative and electrophilic stress, and its pharmacological modulation has attracted considerable attention in drug discovery. Disruption of the Keap1-Nrf2 protein-protein interaction (PPI) has been proposed as an effective strategy to stabilize and activate Nrf2, thereby enhancing the expression of cytoprotective genes. In this review, we provide a comprehensive overview of recent progress in developing direct small-molecule Keap1-Nrf2 PPI inhibitors, spanning diverse chemotypes such as tetrahydroisoquinoline, 1,4-diaminonaphthalene, and other privileged scaffolds. We further summarize advances in Keap1-based PROTACs, one class of which employs targeted Keap1 degradation as an alternative strategy to achieve sustained Nrf2 activation. Special emphasis is placed on the evolution of structure-activity relationships (SAR), optimization of drug-like properties, and validation of pharmacological efficacy in preclinical models, covering disorders such as acute renal and hepatic injury, chronic lung disorders, neurodegeneration, and metabolic dysfunction. Together, these findings underscore the translational potential of Nrf2 activators in various disease contexts and highlight Keap1 as an attractive therapeutic target for future medicinal chemistry efforts.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118485"},"PeriodicalIF":5.9,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731735","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}
Targeted Protein Degradation (TPD) that enables the elimination of disease-causing proteins through hijacking cellular protein degradation machinery, has emerged as a transformative approach in drug discovery. Among the many available TPD strategies, such as proteolysis targeting-chimera (PROTAC), lysosome-targeting chimera (LYTAC), etc., hydrophobic tagging (HyT) has gained increasing attention for its unique mechanism to induce protein degradation by exposing hydrophobic groups on target protein surface, marking them normally smaller in size compared with other chimeras. In this study, we explore the potential of N-Boc-protected amino acids as hydrophobic tags, focusing on their application to degrade the BCR-ABL fusion protein, a key driver of Chronic Myeloid Leukemia (CML). We designed and synthesized a series of degraders by conjugating N-Boc-protected amino acids to the allosteric inhibitor GNF-2, which binds to the myristoyl pocket of BCR-ABL. Among the 20 degraders tested, Boc-protected histidine (Boc2His) demonstrated the most potent degradation activity. Mechanistic studies revealed that Boc2His-induced protein degradation relies on ubiquitination of BCR-ABL and the proteasome pathway, with heat shock proteins Hsp70 and Hsp90 playing a critical role. Notably, Boc2His-based degraders exhibited significant anti-proliferative effects in BCR-ABL-positive K562 cell line and primary CML patient cells, with minimal toxicity to non-cancerous HEK 293T cells. Furthermore, these Boc2His-based degrader effectively degraded drug-resistant BCR-ABL mutants, including T315I and E255K, highlighting its potential to overcome resistance to traditional tyrosine kinase inhibitors. We also extended the application of Boc2His to other targets, such as JAK2 and ALK, demonstrating its versatility as a degradation tag. This study underscores the promise of N-Boc-protected amino acids, particularly Boc-protected histidine, as novel and effective hydrophobic tags for targeted protein degradation, offering a potential therapeutic avenue for CML and other diseases driven by dysregulated proteins.
{"title":"Identification of N-tert-butyloxycarbonyl protected amino acids as novel hydrophobic tags to induce targeted protein degradation","authors":"Hui Sun, Xueyi Luo, Hengjie Hu, Cong Li, Cheng Lyu, Zeming Lin, Cong Wang, Xin Chen, Hao Jiang, Ping Xu, Yan Niu","doi":"10.1016/j.ejmech.2025.118493","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118493","url":null,"abstract":"Targeted Protein Degradation (TPD) that enables the elimination of disease-causing proteins through hijacking cellular protein degradation machinery, has emerged as a transformative approach in drug discovery. Among the many available TPD strategies, such as proteolysis targeting-chimera (PROTAC), lysosome-targeting chimera (LYTAC), etc., hydrophobic tagging (HyT) has gained increasing attention for its unique mechanism to induce protein degradation by exposing hydrophobic groups on target protein surface, marking them normally smaller in size compared with other chimeras. In this study, we explore the potential of <ce:italic>N</ce:italic>-Boc-protected amino acids as hydrophobic tags, focusing on their application to degrade the BCR-ABL fusion protein, a key driver of Chronic Myeloid Leukemia (CML). We designed and synthesized a series of degraders by conjugating <ce:italic>N</ce:italic>-Boc-protected amino acids to the allosteric inhibitor GNF-2, which binds to the myristoyl pocket of BCR-ABL. Among the 20 degraders tested, Boc-protected histidine (Boc<ce:inf loc=\"post\">2</ce:inf>His) demonstrated the most potent degradation activity. Mechanistic studies revealed that Boc<ce:inf loc=\"post\">2</ce:inf>His-induced protein degradation relies on ubiquitination of BCR-ABL and the proteasome pathway, with heat shock proteins Hsp70 and Hsp90 playing a critical role. Notably, Boc<ce:inf loc=\"post\">2</ce:inf>His-based degraders exhibited significant anti-proliferative effects in BCR-ABL-positive K562 cell line and primary CML patient cells, with minimal toxicity to non-cancerous HEK 293T cells. Furthermore, these Boc<ce:inf loc=\"post\">2</ce:inf>His-based degrader effectively degraded drug-resistant BCR-ABL mutants, including T315I and E255K, highlighting its potential to overcome resistance to traditional tyrosine kinase inhibitors. We also extended the application of Boc<ce:inf loc=\"post\">2</ce:inf>His to other targets, such as JAK2 and ALK, demonstrating its versatility as a degradation tag. This study underscores the promise of <ce:italic>N</ce:italic>-Boc-protected amino acids, particularly Boc-protected histidine, as novel and effective hydrophobic tags for targeted protein degradation, offering a potential therapeutic avenue for CML and other diseases driven by dysregulated proteins.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759437","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 : 2025-12-13DOI: 10.1016/j.ejmech.2025.118479
Junda Li, Yanyan Yang, Lei Cheng, Xu Xu, Ke Zhong, Tao Wang, Kailin Chen, Chi Zhang, Chen He, Jinyi Xu, Shengtao Xu, Shanshan Luo
{"title":"Discovery of 8-Quinolinesulfonamide Phenylimidazole-based PKM2 Agonists for the Prevention and Delay of Aortic Dissection","authors":"Junda Li, Yanyan Yang, Lei Cheng, Xu Xu, Ke Zhong, Tao Wang, Kailin Chen, Chi Zhang, Chen He, Jinyi Xu, Shengtao Xu, Shanshan Luo","doi":"10.1016/j.ejmech.2025.118479","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118479","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731734","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 : 2025-12-13DOI: 10.1016/j.ejmech.2025.118486
Kora Reichau, Lucie Crouzier, Tina Gehrig, Alix Flake, Eva Schaller, Johann Meunier, Christelle Bertrand-Gaday, Arnaud Chatonnet, Liga Zvejniece, Christoph Sotriffer, Tangui Maurice, Michael Decker
Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective preventative or curative treatment has yet been identified. Due to the multifactorial nature and complex pathophysiology of the disease, we developed a multi-target ligand that both inhibits human butyrylcholinesterase (hBChE), a key enzyme linked to β-amyloid plaque formation, and activates the sigma-1 receptor (S1R), which modulates neuroinflammatory and protective pathways. To this end, a series of isoindolines were designed and synthesized, and their biological activity was evaluated. The most promising compound, 7c, exhibited significant dual activity, achieving nanomolar IC50 values against hBChE and potent S1R activation. Subsequent in vivo studies in an Aβ25-35 mouse model revealed an improvement in cognitive deficits in both short- and long-term memory at an effective dose of 0.01 mg/kg in WT Swiss-OF1 mice. This dose is 10-fold lower compared to single-target compounds 7a and 7b of this isoindoline series. The lack of neuroprotective effects in BChE knock-out (KO) mice confirmed the involvement of BChE inhibition for compounds 7c effects in WT mice. Further combinatorial studies employing a two-drug combination demonstrated synergy in the neuroprotective effect of the two targets.
{"title":"Targeting Neuroinflammation by Activation of the Sigma-1 Receptor (S1R) and Inhibition of Butyrylcholinesterase (hBChE) Leads to Highly Potent Anti-Amnesic Compounds in an Alzheimer’s Disease Mouse Model","authors":"Kora Reichau, Lucie Crouzier, Tina Gehrig, Alix Flake, Eva Schaller, Johann Meunier, Christelle Bertrand-Gaday, Arnaud Chatonnet, Liga Zvejniece, Christoph Sotriffer, Tangui Maurice, Michael Decker","doi":"10.1016/j.ejmech.2025.118486","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118486","url":null,"abstract":"Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective preventative or curative treatment has yet been identified. Due to the multifactorial nature and complex pathophysiology of the disease, we developed a multi-target ligand that both inhibits human butyrylcholinesterase (<ce:italic>h</ce:italic>BChE), a key enzyme linked to β-amyloid plaque formation, and activates the sigma-1 receptor (S1R), which modulates neuroinflammatory and protective pathways. To this end, a series of isoindolines were designed and synthesized, and their biological activity was evaluated. The most promising compound, <ce:bold>7c</ce:bold>, exhibited significant dual activity, achieving nanomolar IC<ce:inf loc=\"post\">50</ce:inf> values against <ce:italic>h</ce:italic>BChE and potent S1R activation. Subsequent <ce:italic>in vivo</ce:italic> studies in an Aβ<ce:inf loc=\"post\">25-35</ce:inf> mouse model revealed an improvement in cognitive deficits in both short- and long-term memory at an effective dose of 0.01 mg/kg in WT Swiss-OF1 mice. This dose is 10-fold lower compared to single-target compounds <ce:bold>7a</ce:bold> and <ce:bold>7b</ce:bold> of this isoindoline series. The lack of neuroprotective effects in BChE knock-out (KO) mice confirmed the involvement of BChE inhibition for compounds <ce:bold>7c</ce:bold> effects in WT mice. Further combinatorial studies employing a two-drug combination demonstrated synergy in the neuroprotective effect of the two targets.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759486","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 : 2025-12-11DOI: 10.1016/j.ejmech.2025.118472
Manyi Li, Zongguang Tai, Jun Liu, Ruyi Wang, Han Yan, Quangang Zhu, Zhongjian Chen
{"title":"Lysosome-targeted 5,15-diaryltetraacenaphthoporphyrin as a promising immunoinducer for enhanced photodynamic therapy in melanoma","authors":"Manyi Li, Zongguang Tai, Jun Liu, Ruyi Wang, Han Yan, Quangang Zhu, Zhongjian Chen","doi":"10.1016/j.ejmech.2025.118472","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118472","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"111 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731736","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 : 2025-12-11DOI: 10.1016/j.ejmech.2025.118463
Zhengtong Mao , Chunwei Shen , Siyu Liang , Tao Zhou , Jialin Li , Peiyu Yang , Qiwen Shi , Yirong Guo , Xingxian Zhang
Acute lung injury (ALI), a frequent complication among sepsis patients in intensive care units (ICU), is a serious public health problem due to its high mortality rate and the lack of effective treatments in clinic. Cathepsin L (CTSL), which contributes to inflammation, has been demonstrated as a promising therapeutic target for the treatment of ALI. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized. The leading compound 6a showed a high anti-inflammatory activity, achieving inhibition rates of 65 % for IL-6 and 70 % for IL-8 in LPS-stimulated human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Besides, compound 6a successfully suppressed CSTL activity by directly binding to CSTL, and exhibited a good kinase selectivity on CTSL over CTSB, CTSC, CTSS, CTSH and other inflammation-related kinases. The NF-κB and p38 signaling pathways, which lie downstream of CTSL, were also blocked by compound 6a in LPS-treated cells. Moreover, compound 6a significantly alleviates LPS-induced ALI in mice through its anti-inflammatory effects. In conclusion, compound 6a serves as a selective CTSL inhibitor with prominent anti-inflammatory activities and a potential therapeutic agent for the treatment of ALI.
{"title":"Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine derivatives as cathepsin L inhibitor for the treatment of acute lung injury","authors":"Zhengtong Mao , Chunwei Shen , Siyu Liang , Tao Zhou , Jialin Li , Peiyu Yang , Qiwen Shi , Yirong Guo , Xingxian Zhang","doi":"10.1016/j.ejmech.2025.118463","DOIUrl":"10.1016/j.ejmech.2025.118463","url":null,"abstract":"<div><div>Acute lung injury (ALI), a frequent complication among sepsis patients in intensive care units (ICU), is a serious public health problem due to its high mortality rate and the lack of effective treatments in clinic. Cathepsin L (CTSL), which contributes to inflammation, has been demonstrated as a promising therapeutic target for the treatment of ALI. Herein, a series of pyrrolo[2,3-<em>d</em>]pyrimidine derivatives were designed and synthesized. The leading compound <strong>6a</strong> showed a high anti-inflammatory activity, achieving inhibition rates of 65 % for IL-6 and 70 % for IL-8 in LPS-stimulated human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Besides, compound <strong>6a</strong> successfully suppressed CSTL activity by directly binding to CSTL, and exhibited a good kinase selectivity on CTSL over CTSB, CTSC, CTSS, CTSH and other inflammation-related kinases. The NF-κB and p38 signaling pathways, which lie downstream of CTSL, were also blocked by compound <strong>6a</strong> in LPS-treated cells. Moreover, compound <strong>6a</strong> significantly alleviates LPS-induced ALI in mice through its anti-inflammatory effects. In conclusion, compound <strong>6a</strong> serves as a selective CTSL inhibitor with prominent anti-inflammatory activities and a potential therapeutic agent for the treatment of ALI.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118463"},"PeriodicalIF":5.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731739","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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