Pub Date : 2025-10-25DOI: 10.1016/j.ejmcr.2025.100305
Selina Koch , Elena Kullmann , Jürgen Bajorath
As a part of the Illuminating the Druggable Genome initiative, the U.S. National Institutes of Health (NIH), identified 162 understudied human protein and lipid kinases forming the “dark” kinome. In protein kinase (PK) drug discovery, the dark kinome has become a focal point in the search for new PK targets with interesting disease biology and lack of high-quality PK inhibitors (PKIs) for therapeutic intervention. Major criteria for the identification of dark kinases applied by the NIH included the lack of functional information and reagents for functional studies. We have previously introduced an alternative chemistry-centric assessment of understudied PKs that was based on a detailed analysis of the PKI coverage of the human kinome. This concept made it possible to differentiate between PKs based of their degree of chemical exploration. Given the continuing growth of PKI data in the public domain, we have repeated the analysis of chemically explored, underexplored, and unexplored PKs and updated the previous PK classification. As a part of our study, all PK and PKI data curated for our analysis are made publicly available together with the up-to-date chemical exploration-based PK classification and its comparison to the dark kinome. The curated data and kinome classification should be a useful resource for PK target prioritization and medicinal chemistry.
{"title":"Opportunities for protein kinase drug discovery – 2025 update on the chemically underexplored human kinome","authors":"Selina Koch , Elena Kullmann , Jürgen Bajorath","doi":"10.1016/j.ejmcr.2025.100305","DOIUrl":"10.1016/j.ejmcr.2025.100305","url":null,"abstract":"<div><div>As a part of the Illuminating the Druggable Genome initiative, the U.S. National Institutes of Health (NIH), identified 162 understudied human protein and lipid kinases forming the “dark” kinome. In protein kinase (PK) drug discovery, the dark kinome has become a focal point in the search for new PK targets with interesting disease biology and lack of high-quality PK inhibitors (PKIs) for therapeutic intervention. Major criteria for the identification of dark kinases applied by the NIH included the lack of functional information and reagents for functional studies. We have previously introduced an alternative chemistry-centric assessment of understudied PKs that was based on a detailed analysis of the PKI coverage of the human kinome. This concept made it possible to differentiate between PKs based of their degree of chemical exploration. Given the continuing growth of PKI data in the public domain, we have repeated the analysis of chemically explored, underexplored, and unexplored PKs and updated the previous PK classification. As a part of our study, all PK and PKI data curated for our analysis are made publicly available together with the up-to-date chemical exploration-based PK classification and its comparison to the dark kinome. The curated data and kinome classification should be a useful resource for PK target prioritization and medicinal chemistry.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100305"},"PeriodicalIF":0.0,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-22DOI: 10.1016/j.ejmcr.2025.100304
Aleksandra Sęk , Silvia Cammarone , Rafał P. Kampa , Karolina Pytlak , Barbara Kalenik , Joanna Lewandowska , Francesca Ghirga , Isabella Romeo , Omar Atrooz , Piotr Bednarczyk , Adam Szewczyk , Bruno Botta , Deborah Quaglio , Bogusz Kulawiak
Mitochondrial potassium (mitoK) channels play a crucial role in mitochondrial and cellular physiology. One of the best described mitoK channels is the mitochondrial large-conductance calcium-activated potassium (mitoBKCa) channel. It has been shown that activation of the mitoBKCa channel protects the heart and brain tissue against ischemia/reperfusion injury. This channel may be formed in mitochondria by the VEDEC isoform of the α subunit encoded by the KCNMA1 gene. In addition to regulation by canonical channel blockers and potassium channel openers, this channel is regulated by flavonoids, including naringenin. Our work aimed to establish and use a new cellular model to investigate the role of new naringenin derivatives in regulating the activity of the mitoBKCa channel. We developed HEK293 cells stably expressing the VEDEC isoform of the BKCa (HEK293-BK_DEC). Using the patch-clamp technique on isolated mitoplasts from the newly established cell line, we detected the activity of a potassium channel exhibiting all the characteristics of the mitoBKCa channel, such as a conductance of 289 pS, voltage-dependent changes in opening probability, channel activation by calcium ions, and inhibition by paxilline. Additionally, introducing the VEDEC isoform into HEK293 cells led to an increase in the mitochondrial oxygen consumption rate and a change in the expression of certain genes encoding mitochondrial proteins involved in oxidative phosphorylation. Subsequently, we investigated the influence of new naringenin derivatives on the activity of the mitoBKCa channel. We observed that depending on the type of modification of this flavonoid, the channel could be activated or inhibited by the tested naringenin derivatives. In summary, we have developed a new experimental model enabling the study of mitoK channel activity with a defined molecular structure exemplified by the mitoBKCa channel. This model can be used to test new modulators of the mitochondrial potassium channels, which could be employed for further physiological studies in the future.
{"title":"Regulation of mitochondrial potassium BKCa channel by naringenin derivatives: application of a new cellular model","authors":"Aleksandra Sęk , Silvia Cammarone , Rafał P. Kampa , Karolina Pytlak , Barbara Kalenik , Joanna Lewandowska , Francesca Ghirga , Isabella Romeo , Omar Atrooz , Piotr Bednarczyk , Adam Szewczyk , Bruno Botta , Deborah Quaglio , Bogusz Kulawiak","doi":"10.1016/j.ejmcr.2025.100304","DOIUrl":"10.1016/j.ejmcr.2025.100304","url":null,"abstract":"<div><div>Mitochondrial potassium (mitoK) channels play a crucial role in mitochondrial and cellular physiology. One of the best described mitoK channels is the mitochondrial large-conductance calcium-activated potassium (mitoBK<sub>Ca</sub>) channel. It has been shown that activation of the mitoBK<sub>Ca</sub> channel protects the heart and brain tissue against ischemia/reperfusion injury. This channel may be formed in mitochondria by the VEDEC isoform of the α subunit encoded by the KCNMA1 gene. In addition to regulation by canonical channel blockers and potassium channel openers, this channel is regulated by flavonoids, including naringenin. Our work aimed to establish and use a new cellular model to investigate the role of new naringenin derivatives in regulating the activity of the mitoBK<sub>Ca</sub> channel. We developed HEK293 cells stably expressing the VEDEC isoform of the BK<sub>Ca</sub> (HEK293-BK_DEC). Using the patch-clamp technique on isolated mitoplasts from the newly established cell line, we detected the activity of a potassium channel exhibiting all the characteristics of the mitoBK<sub>Ca</sub> channel, such as a conductance of 289 pS, voltage-dependent changes in opening probability, channel activation by calcium ions, and inhibition by paxilline. Additionally, introducing the VEDEC isoform into HEK293 cells led to an increase in the mitochondrial oxygen consumption rate and a change in the expression of certain genes encoding mitochondrial proteins involved in oxidative phosphorylation. Subsequently, we investigated the influence of new naringenin derivatives on the activity of the mitoBK<sub>Ca</sub> channel. We observed that depending on the type of modification of this flavonoid, the channel could be activated or inhibited by the tested naringenin derivatives. In summary, we have developed a new experimental model enabling the study of mitoK channel activity with a defined molecular structure exemplified by the mitoBK<sub>Ca</sub> channel. This model can be used to test new modulators of the mitochondrial potassium channels, which could be employed for further physiological studies in the future.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100304"},"PeriodicalIF":0.0,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1016/j.ejmcr.2025.100302
Attila Egyed , Dóra Judit Kiss , Zsófia Pável , Keve Rajna , Supriya A. Gaitonde , Mariam Dubiel , María Isabel Loza , Edina Szűcs , Éva Borbély , Zsófia Hajna , Grzegorz Satala , Márton Vass , Pál Szabó , Katalin Jósvay , Andrzej J. Bojarski , Holger Stark , Zsuzsanna Helyes , Erika Pintér , Michel Bouvier , György M. Keserű
Dysfunction of dopamine receptors and interruption of normal dopaminergic signaling have been linked to severe neuropsychiatric diseases such as schizophrenia, Parkinson's disease and depression. Although these receptors are among the most drug-targeted families of GPCRs, designing compounds with subtype-specific pharmacological profile remains challenging due to the structural similarities among the subtypes of the family. Considering the structural moieties of cariprazine, a prototypic drug with D3 receptor (D3R) preference, we report a library of bitopic analogues to explore how the orthosteric and secondary binding motifs, coupled with different linkers, affect D2R/D3R selectivity and activity. Compounds with promising dopamine receptor selectivities and binding affinities were further characterized on a GPCR panel and in functional assays. Our efforts resulted in an advanced lead compound (20b) with improved D3R and 5-HT2AR, as well as decreased D2R and 5-HT1AR potencies (EC50) compared to cariprazine. The cleaner receptor profile of this compound retained activities for the most important antidepressant mechanisms that were confirmed by reducing the depression-like behavior in mice.
{"title":"The impact of secondary site interactions on the binding specificity of bitopic dopamine D2/D3 receptor ligands","authors":"Attila Egyed , Dóra Judit Kiss , Zsófia Pável , Keve Rajna , Supriya A. Gaitonde , Mariam Dubiel , María Isabel Loza , Edina Szűcs , Éva Borbély , Zsófia Hajna , Grzegorz Satala , Márton Vass , Pál Szabó , Katalin Jósvay , Andrzej J. Bojarski , Holger Stark , Zsuzsanna Helyes , Erika Pintér , Michel Bouvier , György M. Keserű","doi":"10.1016/j.ejmcr.2025.100302","DOIUrl":"10.1016/j.ejmcr.2025.100302","url":null,"abstract":"<div><div>Dysfunction of dopamine receptors and interruption of normal dopaminergic signaling have been linked to severe neuropsychiatric diseases such as schizophrenia, Parkinson's disease and depression. Although these receptors are among the most drug-targeted families of GPCRs, designing compounds with subtype-specific pharmacological profile remains challenging due to the structural similarities among the subtypes of the family. Considering the structural moieties of cariprazine, a prototypic drug with D<sub>3</sub> receptor (D<sub>3</sub>R) preference, we report a library of bitopic analogues to explore how the orthosteric and secondary binding motifs, coupled with different linkers, affect D<sub>2</sub>R/D<sub>3</sub>R selectivity and activity. Compounds with promising dopamine receptor selectivities and binding affinities were further characterized on a GPCR panel and in functional assays. Our efforts resulted in an advanced lead compound (<strong>20b</strong>) with improved D<sub>3</sub>R and 5-HT<sub>2A</sub>R, as well as decreased D<sub>2</sub>R and 5-HT<sub>1A</sub>R potencies (EC<sub>50</sub>) compared to cariprazine. The cleaner receptor profile of this compound retained activities for the most important antidepressant mechanisms that were confirmed by reducing the depression-like behavior in mice.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100302"},"PeriodicalIF":0.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1016/j.ejmcr.2025.100303
Christian Bailly
Marine-derived bioactive natural products are an essential resource for drug discovery. In particular, marine sponges and associated symbionts can be exploited to discover innovative compounds and new drug candidates. The sponge Hyrtios erectus which is largely distributed in Asian tropical areas, has been extensively investigated as a source of bioactive natural products. A detailed analysis of the natural products isolated from this sponge and their pharmacological properties has been performed. The study led to the identification of over 160 natural products, including over 50 alkaloids, 100 terpenoids and a few other compounds like phenolic alkenes (erectuseneols), chromanones (hyrtiosones) and cyclic peptides (spongitatin-1). The survey introduces multiple series of products, such as the hyrtiosins, hyrtiosulawesine, hyrtiazepine, hyrtioerectines, hyrtioreticulins, hyrtimomines, hyrtinadines, and hainanerectamines among the alkaloids. A large range of sesterterpenes and sesquiterpenes have been isolated, in particular scalarane-type sesterterpenoids such as erectascalaranes A-B, hyrtioscalaranes A-B and hyrtiosins A-F, in addition to a panoply of scalarin and scalaradial derivatives. All these compounds are presented together with their pharmacological properties. Synthetic procedures leading to some of these natural products and analogues are described, notably for hyrtiozulawesine, hyrtinadine A, hytiosine B, and salmahyrtisol A. At the pharmacological level, the most interesting products and associated molecular targets are discussed, such as the targeting of the orphan nuclear receptor Nur77 with 12-epi-scalaradial derivatives. An updated view of the chemical and pharmacological diversity associated with Hyrtios erectus is provided with the goal to promote further researches with this sponge erected as an emblematic figure of the marine natural product chemistry.
{"title":"Pharmacognosy and natural product chemistry of the marine sponge Hyrtios erectus","authors":"Christian Bailly","doi":"10.1016/j.ejmcr.2025.100303","DOIUrl":"10.1016/j.ejmcr.2025.100303","url":null,"abstract":"<div><div>Marine-derived bioactive natural products are an essential resource for drug discovery. In particular, marine sponges and associated symbionts can be exploited to discover innovative compounds and new drug candidates. The sponge <em>Hyrtios erectus</em> which is largely distributed in Asian tropical areas, has been extensively investigated as a source of bioactive natural products. A detailed analysis of the natural products isolated from this sponge and their pharmacological properties has been performed. The study led to the identification of over 160 natural products, including over 50 alkaloids, 100 terpenoids and a few other compounds like phenolic alkenes (erectuseneols), chromanones (hyrtiosones) and cyclic peptides (spongitatin-1). The survey introduces multiple series of products, such as the hyrtiosins, hyrtiosulawesine, hyrtiazepine, hyrtioerectines, hyrtioreticulins, hyrtimomines, hyrtinadines, and hainanerectamines among the alkaloids. A large range of sesterterpenes and sesquiterpenes have been isolated, in particular scalarane-type sesterterpenoids such as erectascalaranes A-B, hyrtioscalaranes A-B and hyrtiosins A-F, in addition to a panoply of scalarin and scalaradial derivatives. All these compounds are presented together with their pharmacological properties. Synthetic procedures leading to some of these natural products and analogues are described, notably for hyrtiozulawesine, hyrtinadine A, hytiosine B, and salmahyrtisol A. At the pharmacological level, the most interesting products and associated molecular targets are discussed, such as the targeting of the orphan nuclear receptor Nur77 with 12-<em>epi</em>-scalaradial derivatives. An updated view of the chemical and pharmacological diversity associated with <em>Hyrtios erectus</em> is provided with the goal to promote further researches with this sponge erected as an emblematic figure of the marine natural product chemistry.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100303"},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145320176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-04DOI: 10.1016/j.ejmcr.2025.100301
Federica Falbo , Jessica Ceramella , Domenico Iacopetta , Nicola Gambacorta , Daniela Trisciuzzi , Orazio Nicolotti , Michele De Luca , Martina Chieffallo , Anna Ramunno , Daniela Bonofiglio , Lorenza Improta , Francesca Aiello , Maria Stefania Sinicropi
Endothelial dysfunction, mainly linked to ionic channel malfunctions, is a key mechanism in the pathogenesis of different vascular disorders including hypertension and atherosclerosis. Several studies confirm a strong correlation between endothelial dysfunction, inflammation and oxidative stress. Regular consumption of antioxidant polyphenol-rich foods has been linked to a reduction in cardiovascular morbidity and mortality. The flavone chrysin, a known Cav1.2 channel inhibitor, was selected in this work as lead compound to generate a library of its derivatives evaluated for their antioxidant and anti-inflammatory properties by means of vitro and cell-based assays. Among them, the best one resulted in the 8-nitrochrysin (1i). Molecular docking revealed that the nitro group plays a critical role in enhancing the binding mode toward iNOS by facilitating the formation of additional polar interactions compared to chrysin. LogP values of chrysin derivatives were also experimentally determined via spectrophotometric method to evaluate the impact of the chemical modifications with respect to the parent compound.
{"title":"Synthesis, bioactivity and docking studies of chrysin derivatives as iNOS inhibitors","authors":"Federica Falbo , Jessica Ceramella , Domenico Iacopetta , Nicola Gambacorta , Daniela Trisciuzzi , Orazio Nicolotti , Michele De Luca , Martina Chieffallo , Anna Ramunno , Daniela Bonofiglio , Lorenza Improta , Francesca Aiello , Maria Stefania Sinicropi","doi":"10.1016/j.ejmcr.2025.100301","DOIUrl":"10.1016/j.ejmcr.2025.100301","url":null,"abstract":"<div><div>Endothelial dysfunction, mainly linked to ionic channel malfunctions, is a key mechanism in the pathogenesis of different vascular disorders including hypertension and atherosclerosis. Several studies confirm a strong correlation between endothelial dysfunction, inflammation and oxidative stress. Regular consumption of antioxidant polyphenol-rich foods has been linked to a reduction in cardiovascular morbidity and mortality. The flavone chrysin, a known Ca<sub>v</sub>1.2 channel inhibitor, was selected in this work as lead compound to generate a library of its derivatives evaluated for their antioxidant and anti-inflammatory properties by means of <em>vitro</em> and cell-based assays. Among them, the best one resulted in the 8-nitrochrysin (<strong>1i</strong>). Molecular docking revealed that the nitro group plays a critical role in enhancing the binding mode toward iNOS by facilitating the formation of additional polar interactions compared to chrysin. LogP values of chrysin derivatives were also experimentally determined <em>via</em> spectrophotometric method to evaluate the impact of the chemical modifications with respect to the parent compound.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100301"},"PeriodicalIF":0.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-27DOI: 10.1016/j.ejmcr.2025.100300
Ruirong Peng , Yu Zhang , Zhenyu He , Yueling Pang , Huanhuan Ma , Ming Fang , Xiaoshan Ding , Yanan Wang , Zhihong Du , Fanming Kong , Liping Chen , Yongqi Liu , Ling Li , Jiawei Li
Systemic diseases are conditions caused by multiple factors (such as immune disorders, inflammation, tumors, etc.) that affect multiple organs, tissues, or systems throughout the body. These diseases are typically characterized by complex pathological states and diverse clinical symptoms. Vascular cell adhesion molecule-1 (VCAM-1) is a multifunctional transmembrane protein that plays a key role in various pathological processes, including inflammation, immune responses, and tumor progression, by mediating immune cell adhesion, regulating the tumor microenvironment, and facilitating signal transduction. This article aims to review the mechanistic roles of VCAM-1 in systemic diseases affecting the circulatory, respiratory, and digestive systems, as well as the association between VCAM-1 and tumor characteristics. Additionally, it discusses targeted therapeutic drugs (including traditional Chinese medicine and Western medicine) that regulate VCAM-1 for disease treatment, providing a theoretical basis for clinical research.
{"title":"Targeted regulatory strategies for VCAM-1 in multisystem diseases","authors":"Ruirong Peng , Yu Zhang , Zhenyu He , Yueling Pang , Huanhuan Ma , Ming Fang , Xiaoshan Ding , Yanan Wang , Zhihong Du , Fanming Kong , Liping Chen , Yongqi Liu , Ling Li , Jiawei Li","doi":"10.1016/j.ejmcr.2025.100300","DOIUrl":"10.1016/j.ejmcr.2025.100300","url":null,"abstract":"<div><div>Systemic diseases are conditions caused by multiple factors (such as immune disorders, inflammation, tumors, etc.) that affect multiple organs, tissues, or systems throughout the body. These diseases are typically characterized by complex pathological states and diverse clinical symptoms. Vascular cell adhesion molecule-1 (VCAM-1) is a multifunctional transmembrane protein that plays a key role in various pathological processes, including inflammation, immune responses, and tumor progression, by mediating immune cell adhesion, regulating the tumor microenvironment, and facilitating signal transduction. This article aims to review the mechanistic roles of VCAM-1 in systemic diseases affecting the circulatory, respiratory, and digestive systems, as well as the association between VCAM-1 and tumor characteristics. Additionally, it discusses targeted therapeutic drugs (including traditional Chinese medicine and Western medicine) that regulate VCAM-1 for disease treatment, providing a theoretical basis for clinical research.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100300"},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26DOI: 10.1016/j.ejmcr.2025.100299
Tao-Tao Ge, Hai-Yan Guo, Chun-Mei Zhang, Shu-Feng Li
sustained-release microsphere technology, with its unique advantages of prolonged controlled release, enhanced therapeutic efficacy, reduced side effects, and improved patient compliance, has emerged as a research hotspot in modern drug delivery. This review systematically summarizes recent advances in sustained-release microspheres in the biomedical field. First, the core concepts and distinct advantages of this approach, compared with conventional drug administration, are elaborated. Subsequently, the principles and features of key preparation techniques, including emulsion–solvent evaporation, spray drying, and advanced microfluidic methods, are highlighted. Furthermore, the applications and validation of microsphere-based systems in diverse therapeutic areas—such as transarterial chemoembolization for cancer, chronic disease management (e.g., diabetes, psychiatric disorders), and local targeted therapies (e.g., ophthalmology, postoperative analgesia)—are critically discussed. Finally, the current challenges and future perspectives of this technology are outlined, providing insights for its further development and clinical translation.
{"title":"Research progress of sustained-release microsphere technology in drug delivery","authors":"Tao-Tao Ge, Hai-Yan Guo, Chun-Mei Zhang, Shu-Feng Li","doi":"10.1016/j.ejmcr.2025.100299","DOIUrl":"10.1016/j.ejmcr.2025.100299","url":null,"abstract":"<div><div>sustained-release microsphere technology, with its unique advantages of prolonged controlled release, enhanced therapeutic efficacy, reduced side effects, and improved patient compliance, has emerged as a research hotspot in modern drug delivery. This review systematically summarizes recent advances in sustained-release microspheres in the biomedical field. First, the core concepts and distinct advantages of this approach, compared with conventional drug administration, are elaborated. Subsequently, the principles and features of key preparation techniques, including emulsion–solvent evaporation, spray drying, and advanced microfluidic methods, are highlighted. Furthermore, the applications and validation of microsphere-based systems in diverse therapeutic areas—such as transarterial chemoembolization for cancer, chronic disease management (e.g., diabetes, psychiatric disorders), and local targeted therapies (e.g., ophthalmology, postoperative analgesia)—are critically discussed. Finally, the current challenges and future perspectives of this technology are outlined, providing insights for its further development and clinical translation.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100299"},"PeriodicalIF":0.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1016/j.ejmcr.2025.100298
Alexandr S. Avksentiev , Vagiz Sh Saberov , Svetlana V. Shishkina , Alexey B. Ryabitsky , Olena Z. Komarovska-Porokhnyavets , Vira I. Lubenets , Vitaliy A. Matvienko , Gennady F. Rayenko , Liubov M. Vakhitova , Nikolai I. Korotkikh
It was found that the in-situ reaction of halogen-containing imidazolium and benzimidazolium salts with silver nitrate, chloride, iodide or perchlorate in the presence of potassium carbonate leads to the corresponding monocarbene (NHC) (LAgX) and bis-NHC silver complexes (L2AgX) including the first strongly sterically shielded bis-NHC complexes (IPr)2AgX. In the presence of o-phenanthroline, carbene-phenanthroline complex (IPr∗)(phen)AgClO4 was obtained. The reactions can be an addition to the known method of Lin with the use of silver oxide. The halogenide silver carbene complexes are also obtained by the exchange of the anion from the ionic perchlorate complexes to halogenide ions (Cl−, I−). The structure of the synthesized compounds is confirmed by the methods of 1H and 13C NMR spectroscopy and for five compounds by the X-ray diffraction study. Most compounds have an ionic character in crystals and in solutions, even for the complex with a sterically shielded silver atom (IPr)2AgNO3 and monocarbene complexes. Synthesized complexes show high antibacterial (MIC up to 1.9 μg/mL on M. luteum) and antifungal activity (MIC up to 0.9 μg/mL on A. niger and 1.9 μg/mL on C. tenuis).
{"title":"Halogen-containing NHC and bis-NHC silver complexes. Synthesis, structure and antimicrobial activity","authors":"Alexandr S. Avksentiev , Vagiz Sh Saberov , Svetlana V. Shishkina , Alexey B. Ryabitsky , Olena Z. Komarovska-Porokhnyavets , Vira I. Lubenets , Vitaliy A. Matvienko , Gennady F. Rayenko , Liubov M. Vakhitova , Nikolai I. Korotkikh","doi":"10.1016/j.ejmcr.2025.100298","DOIUrl":"10.1016/j.ejmcr.2025.100298","url":null,"abstract":"<div><div>It was found that the <em>in-situ</em> reaction of halogen-containing imidazolium and benzimidazolium salts with silver nitrate, chloride, iodide or perchlorate in the presence of potassium carbonate leads to the corresponding monocarbene (NHC) (LAgX) and bis-NHC silver complexes (L<sub>2</sub>AgX) including the first strongly sterically shielded bis-NHC complexes (IPr)<sub>2</sub>AgX. In the presence of o-phenanthroline, carbene-phenanthroline complex (IPr∗)(phen)AgClO<sub>4</sub> was obtained. The reactions can be an addition to the known method of Lin with the use of silver oxide. The halogenide silver carbene complexes are also obtained by the exchange of the anion from the ionic perchlorate complexes to halogenide ions (Cl<sup>−</sup>, I<sup>−</sup>). The structure of the synthesized compounds is confirmed by the methods of <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy and for five compounds by the X-ray diffraction study. Most compounds have an ionic character in crystals and in solutions, even for the complex with a sterically shielded silver atom (IPr)<sub>2</sub>AgNO<sub>3</sub> and monocarbene complexes. Synthesized complexes show high antibacterial (MIC up to 1.9 μg/mL on <em>M. luteum</em>) and antifungal activity (MIC up to 0.9 μg/mL on <em>A. niger</em> and 1.9 μg/mL on <em>C. tenuis</em>).</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100298"},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Endothelial dysfunction and oxidative stress are central contributors to hypertension. Sacha inchi meal protein hydrolysate (SIPH) is recognized for its strong antioxidant activity and potential cardiovascular benefits. This study investigated the protective effects of SIPH on endothelial function and oxidative stress in rats with L-NAME (LN)-induced hypertension. Acute oral toxicity testing showed an LD50 greater than 5000 mg/kg, classifying SIPH as low hazard (Category 5). Male Sprague-Dawley rats received LN (40 mg/kg) and were treated orally with SIPH (100, 300, or 500 mg/kg), captopril (5 mg/kg), or SIPH (500 mg/kg) combined with captopril (2.5 mg/kg) for five weeks. Blood pressure was monitored weekly and validated by carotid artery cannulation. Endothelial function was assessed by vasorelaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP) in isolated aortic rings, while serum malondialdehyde (MDA) and superoxide dismutase (SOD) activity were measured as markers of oxidative stress. LN administration elevated blood pressure impaired ACh-induced vasorelaxation, increased MDA, and reduced SOD activity. SIPH at 500 mg/kg significantly reduced blood pressure, restored endothelial-dependent relaxation, decreased lipid peroxidation, and enhanced antioxidant defense. Notably, the combination of SIPH with captopril exerted synergistic antihypertensive effects, producing greater improvements in vascular reactivity and oxidative balance than either treatment alone. These findings demonstrate that SIPH is a potent vascular protector, acting through synergistic antihypertensive, vasodilatory, and antioxidant mechanisms. Its properties position SIPH as a promising natural dietary intervention for mitigating hypertension and preserving endothelial function.
{"title":"Protective effects of Sacha inchi meal protein hydrolysate against oxidative stress and endothelial dysfunction via MDA suppression and SOD activation in L-NAME-induced hypertensive rats","authors":"Pakaporn Sa-nguanpong , Paweena Wetprasit , Usana Chatturong , Krongkarn Chootip , Napapas Kantip , Worasit Tochampa , Khanitta Ruttarattanamongkol , Tippaporn Bualeong","doi":"10.1016/j.ejmcr.2025.100297","DOIUrl":"10.1016/j.ejmcr.2025.100297","url":null,"abstract":"<div><div>Endothelial dysfunction and oxidative stress are central contributors to hypertension. Sacha inchi meal protein hydrolysate (SIPH) is recognized for its strong antioxidant activity and potential cardiovascular benefits. This study investigated the protective effects of SIPH on endothelial function and oxidative stress in rats with L-NAME (LN)-induced hypertension. Acute oral toxicity testing showed an LD<sub>50</sub> greater than 5000 mg/kg, classifying SIPH as low hazard (Category 5). Male Sprague-Dawley rats received LN (40 mg/kg) and were treated orally with SIPH (100, 300, or 500 mg/kg), captopril (5 mg/kg), or SIPH (500 mg/kg) combined with captopril (2.5 mg/kg) for five weeks. Blood pressure was monitored weekly and validated by carotid artery cannulation. Endothelial function was assessed by vasorelaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP) in isolated aortic rings, while serum malondialdehyde (MDA) and superoxide dismutase (SOD) activity were measured as markers of oxidative stress. LN administration elevated blood pressure impaired ACh-induced vasorelaxation, increased MDA, and reduced SOD activity. SIPH at 500 mg/kg significantly reduced blood pressure, restored endothelial-dependent relaxation, decreased lipid peroxidation, and enhanced antioxidant defense. Notably, the combination of SIPH with captopril exerted synergistic antihypertensive effects, producing greater improvements in vascular reactivity and oxidative balance than either treatment alone. These findings demonstrate that SIPH is a potent vascular protector, acting through synergistic antihypertensive, vasodilatory, and antioxidant mechanisms. Its properties position SIPH as a promising natural dietary intervention for mitigating hypertension and preserving endothelial function.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100297"},"PeriodicalIF":0.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-30DOI: 10.1016/j.ejmcr.2025.100296
Yaqiu Mao , Pengli Wei , Ting Wei , Yalei Wang , Zhenze Qi , Xu Cai , Changkai Jia , Zhiyuan Zhao , Bingkun Li , Min Qiao , Yaxin Zou , Zhihui Mu , Xiaofang Lei , Tingting Yang , Shiyang Sun , Xuesong Feng , Pengyun Li , Zhibing Zheng
As a key driver of tumorigenesis and cancer development, the KRASG12D mutation is ubiquitous existed in KRAS-associated malignancies, highlighting the urgent clinical need for effective KRASG12D targeting drugs. In this study, through rational design and multiple cell type-based antiproliferative evaluation, we identified a novel KRASG12D inhibitor, Y-I-1, which demonstrated remarkable anti-cancer activity. Subsequent computational analyses including molecular dynamics (MD) simulations, binding free energy calculations, umbrella sampling, and protein-ligand docking revealed its excellent binding characteristics, rationalizing the observed potency. Building upon the structure of Y-I-1, we constructed proteolysis-targeting chimera (PROTAC) by conjugating it with different linker moieties and VH032. Among them, degrader Y-D-2 potently and selectively exhibited nanomolar inhibitory IC50, degradation DC50 values, and more than 95 % maximum degradation (Dmax) in KRASG12D-mutant cancer cells via ubiquitin proteasome-involving pathway, accompanied by nanomolar IC50 efficiency for phosphorylated ERK (pERK) inhibition. Mechanistically, Y-D-2 significantly induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, Y-D-2 led to significant tumor growth inhibition in the GP2D xenograft model with well-tolerated dose-schedules with favorable PK properties. This study not only provides an important theoretical basis for the optimal design of KRASG12D degraders, but also highlights its potential for the treatment of KRASG12D-driven cancers.
{"title":"Development of highly potent and selective oncogenic KRASG12D PROTAC degraders","authors":"Yaqiu Mao , Pengli Wei , Ting Wei , Yalei Wang , Zhenze Qi , Xu Cai , Changkai Jia , Zhiyuan Zhao , Bingkun Li , Min Qiao , Yaxin Zou , Zhihui Mu , Xiaofang Lei , Tingting Yang , Shiyang Sun , Xuesong Feng , Pengyun Li , Zhibing Zheng","doi":"10.1016/j.ejmcr.2025.100296","DOIUrl":"10.1016/j.ejmcr.2025.100296","url":null,"abstract":"<div><div>As a key driver of tumorigenesis and cancer development, the KRAS<sup>G12D</sup> mutation is ubiquitous existed in KRAS-associated malignancies, highlighting the urgent clinical need for effective KRAS<sup>G12D</sup> targeting drugs. In this study, through rational design and multiple cell type-based antiproliferative evaluation, we identified a novel KRAS<sup>G12D</sup> inhibitor, <strong>Y-I-1</strong>, which demonstrated remarkable anti-cancer activity. Subsequent computational analyses including molecular dynamics (MD) simulations, binding free energy calculations, umbrella sampling, and protein-ligand docking revealed its excellent binding characteristics, rationalizing the observed potency. Building upon the structure of <strong>Y-I-1</strong>, we constructed proteolysis-targeting chimera (PROTAC) by conjugating it with different linker moieties and VH032. Among them, degrader <strong>Y-D-2</strong> potently and selectively exhibited nanomolar inhibitory IC<sub>50</sub>, degradation DC<sub>50</sub> values, and more than 95 % maximum degradation (D<sub>max</sub>) in KRAS<sup>G12D</sup>-mutant cancer cells via ubiquitin proteasome-involving pathway, accompanied by nanomolar IC<sub>50</sub> efficiency for phosphorylated ERK (pERK) inhibition. Mechanistically, <strong>Y-D-2</strong> significantly induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, <strong>Y-D-2</strong> led to significant tumor growth inhibition in the GP2D xenograft model with well-tolerated dose-schedules with favorable PK properties. This study not only provides an important theoretical basis for the optimal design of KRAS<sup>G12D</sup> degraders, but also highlights its potential for the treatment of KRAS<sup>G12D</sup>-driven cancers.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100296"},"PeriodicalIF":0.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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