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Non-Hydroxamate Inhibitors of IspC Enzyme in the MEP Pathway: Structural Insights and Drug Development Potential MEP 通路中 IspC 酶的非羟氨酸盐抑制剂:结构洞察力与药物开发潜力
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-18 DOI: 10.1111/cbdd.70086
Yaqing Zhou, Jili Wang, Yong Sun, Yarui Cheng, Wenhai Wu
{"title":"Non-Hydroxamate Inhibitors of IspC Enzyme in the MEP Pathway: Structural Insights and Drug Development Potential","authors":"Yaqing Zhou,&nbsp;Jili Wang,&nbsp;Yong Sun,&nbsp;Yarui Cheng,&nbsp;Wenhai Wu","doi":"10.1111/cbdd.70086","DOIUrl":"https://doi.org/10.1111/cbdd.70086","url":null,"abstract":"<div>\u0000 \u0000 <p>1-Deoxy-D-xylulose-5-phosphate reductoisomerase (IspC) is a key enzyme in the MEP pathway, essential for many bacteria, human pathogens, and plants, thus being an attractive drug target. Fosmidomycin, a potent IspC inhibitor with hydroxamate metal-binding pharmacophores (MBPs), has entered clinical trials for malaria but is hampered by pharmacokinetic and toxicity issues of the hydroxamate fragment. This has led to increased interest in non-hydroxamate inhibitors. This review focuses on the crystal structure and active-site binding mode of IspC, and the structural types, inhibitory activities, and structure–activity relationships of non-hydroxamate IspC inhibitors. Early attempts to design such inhibitors involved direct removal or replacement of the hydroxamate MBPs, with varying results. Lipophilic inhibitors, bisubstrate inhibitors, and those developed for herbicidal applications have shown promise. However, challenges remain due to the sensitivity of the enzyme active site to ligand interactions. Future research could draw from other metalloenzyme studies to develop novel and efficient non-hydroxamate IspC inhibitors.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Small Molecule Inhibitors Targeting Cdc2-Like Kinase 4: Advances, Challenges, and Opportunities
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-17 DOI: 10.1111/cbdd.70087
Yu Jiang, Zihua Tang, Minggao Jiang, Jing Wang, Yanhai Wang
{"title":"Small Molecule Inhibitors Targeting Cdc2-Like Kinase 4: Advances, Challenges, and Opportunities","authors":"Yu Jiang,&nbsp;Zihua Tang,&nbsp;Minggao Jiang,&nbsp;Jing Wang,&nbsp;Yanhai Wang","doi":"10.1111/cbdd.70087","DOIUrl":"https://doi.org/10.1111/cbdd.70087","url":null,"abstract":"<div>\u0000 \u0000 <p>Cdc2-like kinase 4 (Clk4), a key member of the CMGC kinase family, plays a crucial role in alternative splicing, which profoundly influences various physiological processes, including cellular signaling, proliferation, and survival. Its involvement in these vital functions has positioned Clk4 as an important target for therapeutic intervention in a range of diseases, such as neurodegenerative disorders, viral and parasitic infections, and cancer. This review highlights recent advancements in Clk4 inhibitors, covering both natural, and synthetic compounds. It further examines the core scaffolds and essential functional groups of Clk4 small-molecule inhibitors, emphasizing the most promising chemical structures. Additionally, the review explores the structure–activity relationships (SARs) and molecular binding modes of existing Clk4 inhibitors, offering insights and strategies for the development of novel Clk4-targeted drugs. This review highlights recent advancements in small molecule inhibitors targeting Clk4, emphasizing their potential in treating cancers and neurodegenerative diseases. It explores SARs, binding modes, and challenges in developing selective Clk4 inhibitors, offering insights for future therapeutic strategies.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Synthesis of New Thiazole-Pyrazole Analogues: Molecular Modelling, Antiproliferative/Antiviral Activities, and ADME Studies
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-14 DOI: 10.1111/cbdd.70090
Hind A. Siddiq, Mohammed A. Imam, Shaker T. Alsharif, Roba M. S. Attar, Renad Almughathawi, Nadiyah M. Alshammari, Nuha M. Halawani, Nashwa M. El-Metwaly
{"title":"Synthesis of New Thiazole-Pyrazole Analogues: Molecular Modelling, Antiproliferative/Antiviral Activities, and ADME Studies","authors":"Hind A. Siddiq,&nbsp;Mohammed A. Imam,&nbsp;Shaker T. Alsharif,&nbsp;Roba M. S. Attar,&nbsp;Renad Almughathawi,&nbsp;Nadiyah M. Alshammari,&nbsp;Nuha M. Halawani,&nbsp;Nashwa M. El-Metwaly","doi":"10.1111/cbdd.70090","DOIUrl":"https://doi.org/10.1111/cbdd.70090","url":null,"abstract":"<div>\u0000 \u0000 <p>Twelve thiazole-pyrazole analogues <b>4</b>, <b>6</b>, and <b>8</b> were synthesized by introducing various pyrazole systems into the core, 2-((4-acetylphenyl)amino)-4-methylthiazole (<b>2</b>), through many synthetic approaches. The density functional theory (DFT) study of the synthesized analogues revealed coincided configurations of their highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), except for the nitro derivatives, in which the intramolecular charge-transfer (CT) may be denoted as π → π* and <i>n</i> → π*. In addition, the in vitro antiproliferative efficacy towards some cancer cell lines was examined (Panc-1, HT-29, MCF-7) and the non-cancerous (WI-38), using Dasatinib (Reference). The analogues <b>4c</b> and <b>4d</b> demonstrated the most potent anticancer effect, particularly against Panc-1 and MCF-7 cells. Moreover, the antiviral activity against H5N1, using a plaque reduction assay, showed that analogue <b>6a</b> exhibited the most potent antiviral activity (100% inhibition and TC<sub>50</sub> = 61 μg/μL), comparable to the reference drug amantadine (TC<sub>50</sub> = 72 μg/μL, 100% inhibition). Furthermore, the molecular docking disclosed that the analogues exhibited a range of interactions, such as H-bonding and π-π stacking, with binding affinities between −4.8558 and − 8.3673 kcal/mol. Additionally, the SwissADME predictions indicated that the synthesized analogues possess promising drug-like characteristics, but analogues <b>4a–d</b> and <b>8c</b> demonstrated inadequate solubility and bioavailability, which restricts their use as viable oral medications.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Nature of Nanodisc Lipids Influences Fragment-Based Drug Discovery Results
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-14 DOI: 10.1111/cbdd.70080
Tim G. J. Knetsch, Henri van Son, Masakazu Kobayashi, Marcellus Ubbink
{"title":"The Nature of Nanodisc Lipids Influences Fragment-Based Drug Discovery Results","authors":"Tim G. J. Knetsch,&nbsp;Henri van Son,&nbsp;Masakazu Kobayashi,&nbsp;Marcellus Ubbink","doi":"10.1111/cbdd.70080","DOIUrl":"https://doi.org/10.1111/cbdd.70080","url":null,"abstract":"<p>Membrane proteins (MPs) are important yet challenging targets for drug discovery. MPs can be reconstituted in protein-lipid Nanodiscs (NDs), which resemble the native membrane environment. Drug-membrane interactions can affect the apparent binding stoichiometry and affinity, as well as the kinetics of ligands for a particular target, which is important for the extrapolation to pharmacokinetic studies. To investigate the role of the membrane, we have applied fragment-based drug discovery (FBDD) methods to cytochrome P450 3A4 (CYP3A4), reconstituted in NDs composed of different phosphocholine lipids: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC). Surface plasmon resonance screening of fragments and marketed drugs revealed extensive binding to the empty ND, correlating with analyte hydrophobicity, and the binding was critically dependent on ND lipid composition. POPC NDs showed much higher binding of fragments than DMPC and DPhPC NDs, resulting in a lower hit rate for CYP3A4 in POPC NDs, which demonstrated that the choice of the ND lipid is crucial to the outcome of a screen. The number of binders that were rejected based on atypical binding kinetics was lower for monomeric CYP3A4 in NDs than for non-native oligomeric CYP3A4 without the ND. Several fragments were exclusively identified as hits for CYP3A4 in the presence of the ND membrane. It is concluded that the nature of the ND is a critical factor for fragment screening of membrane proteins.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pyrrole-Tethered Bisbenzoxazole Derivatives: Apoptosis-Inducing Agents Targeting Breast Cancer Cells
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-13 DOI: 10.1111/cbdd.70078
Burak Kuzu, Derya Yetkin, Ceylan Hepokur, Oztekin Algul
{"title":"Pyrrole-Tethered Bisbenzoxazole Derivatives: Apoptosis-Inducing Agents Targeting Breast Cancer Cells","authors":"Burak Kuzu,&nbsp;Derya Yetkin,&nbsp;Ceylan Hepokur,&nbsp;Oztekin Algul","doi":"10.1111/cbdd.70078","DOIUrl":"https://doi.org/10.1111/cbdd.70078","url":null,"abstract":"<p>This study presents the design, synthesis, and biological evaluation of a series of novel pyrrole-tethered bisbenzoxazole (PTB) derivatives as potential apoptosis-inducing agents targeting the MCF-7 human breast cancer cell line. The anticancer activity of these compounds was evaluated in vitro using the MTT assay, with tamoxifen serving as the reference therapeutic agent. Compounds <b>B8</b>, <b>B14</b>, and <b>B18</b> demonstrated remarkable cytotoxicity against MCF-7 cells, exhibiting approximately 8-fold lower IC<sub>50</sub> values compared to tamoxifen, while showing minimal effects on healthy fibroblasts. Further investigations revealed that these compounds effectively induced early-stage apoptosis and selectively arrested the cell cycle at the G1 phase in cancer cells. Gene expression analysis confirmed selective activation of the caspase-9-mediated apoptotic pathway in MCF-7 cells, providing insights into their underlying molecular mechanisms. These findings highlight the promising potential of PTB derivatives as potent anticancer agents, laying the groundwork for the development of targeted therapies for breast cancer that leverage apoptosis induction for improved therapeutic outcomes.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of Potential PBP2a Inhibitors Against Methicillin-Resistant Staphylococcus aureus via Drug Repurposing and Combination Therapy
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-12 DOI: 10.1111/cbdd.70088
Fangfang Jiao, Pinkai Wang, Derong Zeng, Yiqiong Bao, Yan Zhang, Jun Tao, Jingjing Guo
{"title":"Identification of Potential PBP2a Inhibitors Against Methicillin-Resistant Staphylococcus aureus via Drug Repurposing and Combination Therapy","authors":"Fangfang Jiao,&nbsp;Pinkai Wang,&nbsp;Derong Zeng,&nbsp;Yiqiong Bao,&nbsp;Yan Zhang,&nbsp;Jun Tao,&nbsp;Jingjing Guo","doi":"10.1111/cbdd.70088","DOIUrl":"https://doi.org/10.1111/cbdd.70088","url":null,"abstract":"<div>\u0000 \u0000 <p>Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) achieves high-level resistance against β-lactam antibiotics through the expression of penicillin-binding protein 2a (PBP2a), which features a closed active site that impedes antibiotic binding. Herein, we implemented a strategy that combines drug repurposing with synergistic therapy to identify potential inhibitors targeting PBP2a's allosteric site from an FDA-approved drug database. Initially, retrospective verifications were conducted, employing different Glide docking methods (HTVS, SP, and XP) and two representative PBP2a structures. The combination of Glide SP and one representative PBP2a conformation showed the highest efficacy in identifying active compounds. The optimized parameters were then utilized to screen FDA-approved drugs, and 15 compounds were shortlisted for potential combination therapy with cefazolin, an ineffective cephalosporin against MRSA. Through biological assays—checkerboard, time-kill assays, and live/dead bacterial staining—we discovered that four compounds exhibited robust bactericidal activity (FICI &lt; 0.5) compared to both untreated control and monotherapy with cefazolin alone. Scanning electron microscopy (SEM) confirmed that while cefazolin alone did not cause visible damage to MRSA cells, the combination treatment markedly induced cell lysis. Additional MM-GBSA studies underscored the strong binding affinity of mitoxantrone to the allosteric site. These findings introduce a combination therapy approach that potentially restores MRSA's susceptibility to β-lactam antibiotics.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting Blood-Stage Malaria: Design, Synthesis, Characterization, In Vitro, and In Silico Evaluation of Pyrrolidinodiazenyl Chalcones
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-12 DOI: 10.1111/cbdd.70081
Ahammed Ameen Thottasseri, Vinoth Rajendran, Deepthi Ramesh, Anju Agnes Tom, Roshiny Roy Thomas, Sreetama Ray, Gopika Gopan, Maheswaran Mani, Tharanikkarasu Kannan
{"title":"Targeting Blood-Stage Malaria: Design, Synthesis, Characterization, In Vitro, and In Silico Evaluation of Pyrrolidinodiazenyl Chalcones","authors":"Ahammed Ameen Thottasseri,&nbsp;Vinoth Rajendran,&nbsp;Deepthi Ramesh,&nbsp;Anju Agnes Tom,&nbsp;Roshiny Roy Thomas,&nbsp;Sreetama Ray,&nbsp;Gopika Gopan,&nbsp;Maheswaran Mani,&nbsp;Tharanikkarasu Kannan","doi":"10.1111/cbdd.70081","DOIUrl":"https://doi.org/10.1111/cbdd.70081","url":null,"abstract":"<div>\u0000 \u0000 <p>Malaria is a pervasive and deadly threat to the global population, and the resources available to treat this disease are limited. There is widespread clinical resistance to the most commonly prescribed antimalarial drugs. To address this issue, we synthesized a range of 4′-pyrrolidinodiazenyl chalcones using a covalent bitherapy approach to study their potential antimalarial properties. We examined the structure–activity relationships of these compounds, which could explain their antimalarial activities. The in vitro blood stage antimalarial activity of the compounds was evaluated against the mixed-blood stage culture (ring, trophozoites and schizonts) of <i>Plasmodium falciparum</i> 3D7, and the 50% inhibitory concentrations (IC<sub>50</sub>s) ranged from 3.3 to 22.2 μg/mL after 48 h of exposure. Compounds <b>11</b>, <b>19</b>, and <b>22</b> displayed pronounced IC<sub>50</sub> values of 7.6 μg/mL, 6.4 μg/mL, and 3.3 μg/mL, respectively. The in vitro cytotoxicity of the active compounds was evaluated on human-derived Mo7e cells and murine-derived BA/F3 cells. Compounds <b>11</b> and <b>19</b> were found to be noncytotoxic (&gt; 40 μg/mL), whereas compound <b>22</b> displayed cytotoxicity at higher concentrations. Moreover, these compounds exerted negligible hemolytic effects on human RBCs at their active concentrations. Molecular docking of these compounds revealed good hydrophobic and hydrogen bonding interactions with the binding sites of <i>Plasmodium falciparum</i>-dihydrofolate reductase, providing a rationale for their antimalarial activity, which is consistent with the in vitro results.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Machine Learning-Based Discovery of a Novel Noncovalent MurA Inhibitor as an Antibacterial Agent
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-12 DOI: 10.1111/cbdd.70084
Qingxin Liu, Aoqi Luo, Hongwei Jin, Xinxin Si, Ming Li
{"title":"Machine Learning-Based Discovery of a Novel Noncovalent MurA Inhibitor as an Antibacterial Agent","authors":"Qingxin Liu,&nbsp;Aoqi Luo,&nbsp;Hongwei Jin,&nbsp;Xinxin Si,&nbsp;Ming Li","doi":"10.1111/cbdd.70084","DOIUrl":"https://doi.org/10.1111/cbdd.70084","url":null,"abstract":"<div>\u0000 \u0000 <p>The bacterial cell wall is crucial for maintaining the integrity of bacterial cells. UDP-N-acetylglucosamine 1-carboxyethylene transferase (MurA) is an important enzyme involved in bacterial cell wall synthesis. Therefore, it is an important target for antibacterial drug research. Although many MurA inhibitors have been discovered, only fosfomycin is still used as a MurA inhibitor in clinical practice. Owing to the long-term use of fosfomycin, the emergence of fosfomycin resistance is worrisome. Therefore, it is still necessary to discover new MurA inhibitors with different types of action than fosfomycin. In this study, we used AutoMolDesigner to construct a machine learning model combined with molecular docking to screen for noncovalent MurA inhibitors. We subsequently conducted the MurA inhibition activity assay and identified compound <b>L16</b> (N-(3-(benzo[d]oxazol-2-yl)-4-hydroxyphenyl) carbamoyl-4-methylbenzamide) as a moderately active MurA inhibitor (IC<sub>50</sub> = 26.63 ± 1.60 μM). The compound was structurally different from other known MurA inhibitors. We used molecular dynamics simulation to reveal possible interactions between the compound and MurA. In addition, we also found that compound <b>L16</b> was nontoxic to human liver cancer cells (HepG2) (IC<sub>50</sub> &gt; 100 μM). In conclusion, through virtual screening and in vitro biological evaluation, we identified a novel structural type of MurA inhibitor which may become a candidate drug for inhibiting bacterial cell wall synthesis.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Moscatilin Induces Ferroptosis in Clear Cell Renal Cell Carcinoma via the JAK–STAT Signaling Pathway
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-12 DOI: 10.1111/cbdd.70071
Pei Chen, Jin Yang, Lin Chen, Chenhuan Liu, Zhihao Li, Xiaoming Long, Jinbang Wu, Bo Wu, Jianjun Wu
{"title":"Moscatilin Induces Ferroptosis in Clear Cell Renal Cell Carcinoma via the JAK–STAT Signaling Pathway","authors":"Pei Chen,&nbsp;Jin Yang,&nbsp;Lin Chen,&nbsp;Chenhuan Liu,&nbsp;Zhihao Li,&nbsp;Xiaoming Long,&nbsp;Jinbang Wu,&nbsp;Bo Wu,&nbsp;Jianjun Wu","doi":"10.1111/cbdd.70071","DOIUrl":"https://doi.org/10.1111/cbdd.70071","url":null,"abstract":"<div>\u0000 \u0000 <p>Moscatilin, a biphenyl compound derived from <i>Dendrobium nobile</i>, exhibits significant anti-tumor activity. However, the specific role of moscatilin in clear cell renal cell carcinoma (ccRCC) and its underlying molecular mechanisms have not been fully studied. This study aims to fill this gap by demonstrating through a series of experiments that moscatilin can effectively inhibit the proliferation and migration of ccRCC and induce its apoptosis process. More importantly, we found that moscatilin can also trigger ferroptosis in ccRCC, a process accompanied by significant increases in Fe<sup>2+</sup>, MDA (a lipid peroxidation product), and ROS (reactive oxygen species) levels, as well as decreases in mitochondrial membrane potential and GSH (glutathione) levels. These changes strongly suggest a key role for moscatilin in inducing ferroptosis. To further explore its underlying mechanism, we speculate that moscatilin may inhibit the phosphorylation level of the JAK–STAT signaling pathway, thereby blocking the function of the key protein SLC7A11 in the ferroptosis signaling pathway, which promotes the occurrence of ferroptosis. This discovery not only reveals a new mechanism of moscatilin in the treatment of ccRCC but also provides new ideas for the development of related drugs in the future. In summary, based on the important discovery that moscatilin can induce ferroptosis in ccRCC, we have reason to believe that moscatilin has the potential to become a new type of drug for the treatment of ccRCC.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tanshinone IIA Reverses Osteogenic Differentiation of Bone Marrow Mesenchymal Stromal Cells Impaired by Glucocorticoids via the ERK1/2-CREB Signaling Pathway
IF 3.2 4区 医学
Chemical Biology & Drug Design Pub Date : 2025-03-06 DOI: 10.1111/cbdd.70069
Xiaodong Li, Xinyue Yang, Zelin Liu, Hongpeng Liu, Hang Lv, Xue Li, Xilin Xu, Yiwei Shen
{"title":"Tanshinone IIA Reverses Osteogenic Differentiation of Bone Marrow Mesenchymal Stromal Cells Impaired by Glucocorticoids via the ERK1/2-CREB Signaling Pathway","authors":"Xiaodong Li,&nbsp;Xinyue Yang,&nbsp;Zelin Liu,&nbsp;Hongpeng Liu,&nbsp;Hang Lv,&nbsp;Xue Li,&nbsp;Xilin Xu,&nbsp;Yiwei Shen","doi":"10.1111/cbdd.70069","DOIUrl":"https://doi.org/10.1111/cbdd.70069","url":null,"abstract":"<div>\u0000 \u0000 <p>Glucocorticoids-induced osteoporosis poses a critical health issue due to its detrimental impact on bone marrow mesenchymal stem cells (BMSCs); Tanshinone IIA (TSA) emerges as a promising therapeutic intervention, demonstrating its capacity to reverse osteogenic differentiation impairment. The aim is to determine whether TSA enhances the osteogenic differentiation of BMSCs damaged by dexamethasone (DEX) through the ERK1/2 –CREB signaling pathway. BMSCs were treated with varying concentrations of DEX (0.1–30 μM) and TSA (0.04–5 μM) for 18 or 36 h. Cell viability was assessed using the MTT assay. Osteogenic differentiation was evaluated through Alizarin Red S staining and quantified by qRT-PCR for osteogenic markers such as Runx2 and ALP. Apoptosis was measured by Annexin V-FITC/PI staining and TUNEL/DAPI co-staining. The ERK1/2-CREB signaling pathway was examined using Western blot and immunofluorescence. TSA at 5 μM significantly bolstered BMSCs viability and osteogenic differentiation, reversing the deleterious effects of 30 μM DEX. TSA pre-treatment decreased apoptosis and ROS levels, and importantly, it enhanced the ERK1/2-CREB signaling pathway, as evidenced by increased phosphorylation of ERK1/2 and CREB. The ERK1/2 inhibitor PD98059 and siCREB abrogated TSA's protective effects, highlighting the pathway's significance. These findings indicate that TSA, through the ERK1/2-CREB axis, provides a protective strategy against DEX-induced impairment in BMSCs. TSA's modulation of the ERK1/2 –CREB pathway reverses DEX-induced osteogenic inhibition and apoptosis in BMSCs, suggesting its therapeutic efficacy against glucocorticoid-induced bone disorders.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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