Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第5页

Identification of broad-spectrum M^pro inhibitors: a focus on high-risk coronaviruses and conserved interactions. 广谱Mpro抑制剂的鉴定：重点关注高风险冠状病毒和保守相互作用

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-05-21 DOI: 10.1080/14756366.2025.2503961

Man Liu, Li Zhao, Xupeng Huang, Zhenhao Tang, Yihang Zhong, Mengrong Yan, Shun Liu, Shunjing Wang, Zeyun Sun, Zixuan Rao, Linyi Yu, Yuying Fang, Wei Zhang, Hongbo Zhang, Wei Peng

{"title":"Identification of broad-spectrum Mpro inhibitors: a focus on high-risk coronaviruses and conserved interactions.","authors":"Man Liu, Li Zhao, Xupeng Huang, Zhenhao Tang, Yihang Zhong, Mengrong Yan, Shun Liu, Shunjing Wang, Zeyun Sun, Zixuan Rao, Linyi Yu, Yuying Fang, Wei Zhang, Hongbo Zhang, Wei Peng","doi":"10.1080/14756366.2025.2503961","DOIUrl":"10.1080/14756366.2025.2503961","url":null,"abstract":"The COVID-19 pandemic underscores the urgent need to develop broad-spectrum antivirals against coronaviruses (CoVs) to prepare for future outbreaks. In this study, we presented a systematic approach to developing broad-spectrum Mpro inhibitors, with a focus on high-risk CoVs. We optimised S-217622 as a lead compound, with the goal of enhancing conserved interactions within the S1, S2, and S3/S4 pockets of Mpro, leading to significantly improved inhibitory potency against representative CoVs. Compound 25 exhibited submicromolar activity across all ten CoVs, with IC50 values below 0.1 μM for six of them. The X-ray co-crystal structure of SARS-CoV-2 Mpro in complex with compound 25 revealed the structural basis of conserved interactions contributing to its broad-spectrum activity. This study demonstrates the feasibility of reinforcing conserved interactions to develop Mpro inhibitors with broad-spectrum activity and provides valuable strategies for combating future pandemics caused by unknown CoVs.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2503961"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Myeloperoxidase as a therapeutic target for oxidative damage in Alzheimer's disease. 髓过氧化物酶作为阿尔茨海默病氧化损伤的治疗靶点。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-14 DOI: 10.1080/14756366.2025.2456282

Astrid Mayleth Rivera Antonio, Itzia Irene Padilla Martínez, Mónica A Torres-Ramos, Martha Cecilia Rosales-Hernández

引用次数: 0

Chalcones inhibit firefly bioluminescence dependent on A and B-ring substitution pattern - a structure-activity study combined with molecular docking. 查尔酮抑制萤火虫生物发光依赖于A和b环取代模式-结合分子对接的结构-活性研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-09 DOI: 10.1080/14756366.2025.2509657

Corinna Urmann, Michael Kirchinger, Herbert Riepl

{"title":"Chalcones inhibit firefly bioluminescence dependent on A and B-ring substitution pattern - a structure-activity study combined with molecular docking.","authors":"Corinna Urmann, Michael Kirchinger, Herbert Riepl","doi":"10.1080/14756366.2025.2509657","DOIUrl":"10.1080/14756366.2025.2509657","url":null,"abstract":"Chalcones represent a privileged scaffold in medicinal chemistry, with pyranochalcones, featuring an additional chromane-like ring, identified as neurogenic and neuroprotective. Reporter gene assays, often used to study these and other effects, can produce false positives due to firefly luciferase stabilisation by inhibitors. The present study demonstrates that pyranochalcones inhibit firefly luciferase activity, with inhibition levels ranging from none to 100% and IC50 values of 7.82 µM to 92.99 µM. Furthermore, molecular docking offers potential structure-based explanations for the observed selectivity of compounds towards firefly luciferase inhibition. Even slight modifications in the molecular structure lead to significant changes in luciferase inhibition, underscoring the importance of these findings for understanding structure-activity relationships in reporter gene assays. Accordingly, caution is advised when using reporter gene assays based on firefly luciferase and pyranochalcones, as the IC50 values are within the range of concentrations commonly used in both in vivo and in vitro assays.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2509657"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening. 利用高通量虚拟筛选技术鉴定靶向泛素特异性蛋白酶11 （USP11）的化学支架

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-30 DOI: 10.1080/14756366.2025.2518191

Hobin Lee, Sunghoon Hurh, Soomin Kang, Jihwan Yoon, Jong-Ik Hwang, Derek T Logan, Hong-Rae Kim

{"title":"Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening.","authors":"Hobin Lee, Sunghoon Hurh, Soomin Kang, Jihwan Yoon, Jong-Ik Hwang, Derek T Logan, Hong-Rae Kim","doi":"10.1080/14756366.2025.2518191","DOIUrl":"10.1080/14756366.2025.2518191","url":null,"abstract":"USP11 is a promising therapeutic target implicated in Alzheimer's disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2518191"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528161","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}

引用次数: 0

Discovery and biological evaluation of a novel and highly potent JAK2 inhibitor for the treatment of triple negative breast cancer. 一种新型高效JAK2抑制剂治疗三阴性乳腺癌的发现和生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-04-29 DOI: 10.1080/14756366.2025.2488127

Yingxiang Miao, Shudan Yang, Fang Zhang, Jindong Li, Yan Zhang

{"title":"Discovery and biological evaluation of a novel and highly potent JAK2 inhibitor for the treatment of triple negative breast cancer.","authors":"Yingxiang Miao, Shudan Yang, Fang Zhang, Jindong Li, Yan Zhang","doi":"10.1080/14756366.2025.2488127","DOIUrl":"https://doi.org/10.1080/14756366.2025.2488127","url":null,"abstract":"Janus kinase 2 (JAK2) is considered an attractive target for the treatment of triple-negative breast cancer (TNBC). Herein, we discovered six JAK2 inhibitors using structure-based virtual screening and molecular docking. Among them, JNN-5 was the best compound. It indicated strong inhibitory effects on JAK2 in the nanomolar range (IC50 = 0.41 ± 0.03 nM), and high selectivity for JAK2 over JAK1 and JAK3 (selectivity index (SI) > 73.17). Moreover, molecular dynamics (MD) simulation exhibited that JNN-5 bound with high stability to JAK2 JH1. Cellular assays revealed that JNN-5 displayed strong antiproliferative activities in the TNBC cell lines (MDA-MB-468, MDA-MB-213, HCC70, MDA-MB-157). JNN-5 significantly reduced the migration of HUVECs with the dose-dependence. JNN-5 had a significant inhibitory effect on multidrug-resistant MDA-MB-231/ADR (IC50 = 0.37 ± 0.02 μM). These data demonstrate that JNN-5 may be a highly effective and selective antitumor compound for the treatment of TNBC.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2488127"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies. Selisistat是一种SIRT1抑制剂，可增强紫杉醇在腔内和三阴性乳腺癌中的活性：计算机、体外和体内研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-12 DOI: 10.1080/14756366.2025.2458554

Anna Wawruszak, Jarogniew Luszczki, Damian Bartuzi, Joanna Kalafut, Estera Okon, Arkadiusz Czerwonka, Andrzej Stepulak

{"title":"Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies.","authors":"Anna Wawruszak, Jarogniew Luszczki, Damian Bartuzi, Joanna Kalafut, Estera Okon, Arkadiusz Czerwonka, Andrzej Stepulak","doi":"10.1080/14756366.2025.2458554","DOIUrl":"10.1080/14756366.2025.2458554","url":null,"abstract":"Sirtuins (SIRTs) are NAD+-dependent histone deacetylases, which play a key role in cancer progression; however, their prognostic values in breast cancer (BC) remain a subject of debate and controversy. Accumulative evidence suggests that each sirtuin possesses individual character, implicating its role in the regulation of multifaceted biological functions leading to BC initiation, progression and metastasis. Selisistat (EX527) is a potent, cell permeable, highly selective SIRT1 inhibitor. In the study, the tumour-suppressive effects of the SIRT1 inhibitor EX527 (selisistat) alone and in combination with paclitaxel (PAX) in different breast cancer cell lines and zebrafish xenograft models were investigated. The type of pharmacological drug-drug interaction between EX527 and PAX was determined using the isobolographic method. EX527 and PAX used individually inhibited proliferation, induced apoptosis and caused cell cycle arrest in G1 and subG1/G2 phases. Interestingly, the combination of these compounds used in the 1:1 dose-ratio augmented all these effects (IC50add 29.52 ± 3.29 - 38.45 ± 5.26). The co-treatment of EX527 with PAX generated desirable additive drug-drug interaction. The simultaneous application of EX527 and PAX induced a stronger inhibition of tumour growth compared to individual treatments in zebrafish xenografts. In silico analysis revealed a protein-protein interaction pathway (SIRT1-AKT-S1PR1-GNAI1/GNAO1-Tubulin) connecting molecular targets of both ligands. To summarise, the combination of EX527 and PAX more effectively impairs breast cancer cell growth compared to individual treatments. However, further investigations are required to clarify the specific targets and molecular mechanisms underlying the activity of EX527:PAX in other preclinical models.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2458554"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Design and synthesis of novel HDAC6 inhibitor dimer as HDAC6 degrader for cancer treatment by palladium catalysed dimerisation. 新型HDAC6抑制剂二聚体的设计与合成用于钯催化二聚治疗癌症的HDAC6降解剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-27 DOI: 10.1080/14756366.2025.2468355

Ching Lin, Jui-Ling Hsu, Yu-Tung Hsu, Kuo-Chen Fan, Sian-Siou Wu, Miao-Hsia Lin, Jih-Hwa Guh, Chao-Wu Yu

{"title":"Design and synthesis of novel HDAC6 inhibitor dimer as HDAC6 degrader for cancer treatment by palladium catalysed dimerisation.","authors":"Ching Lin, Jui-Ling Hsu, Yu-Tung Hsu, Kuo-Chen Fan, Sian-Siou Wu, Miao-Hsia Lin, Jih-Hwa Guh, Chao-Wu Yu","doi":"10.1080/14756366.2025.2468355","DOIUrl":"10.1080/14756366.2025.2468355","url":null,"abstract":"The enigmatic histone deacetylase 6 (HDAC6) is one of a kind among its family. Recent reports revealed that HDAC6 CD1 exhibits E3 ligase activity. Inspired by these researches, we attempted to develop drugs targeting HDAC6 via novel mechanism. Herein, we report a palladium catalysed transformation and purification method for hydroxamic acid dimers, and series of HDAC6 inhibitor-based dimer showing outstanding biological activities and capability of inducing auto-degradation. Our proof-of-concept was highlighted with 2-amino benzamide-based HDAC6 inhibitor dimers that exhibit great HDAC6 inhibition activity (3.9-15.4 nM), good HDAC1/6 selectivity (95-577), and excellent cytotoxicity against human hormone-resistant prostate cancer (HRPC) PC-3 and non-small cell lung cancer (NSCLC) A549 cell lines (5.9-11.3 and 6.6-17.9 μM, respectively) while simultaneously inducing HDAC6 degradation. These dimers not only induce apoptosis and autophagy but also interfere with kinetochore attachment by the detection of BUBR1 phosphorylation at S670.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2468355"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of novel biphenyl compounds bearing hydroxamic acid moiety as the first PD-L1/class I HDACs dual inhibitors. 发现含有羟肟酸片段的新型联苯化合物作为首个PD-L1/ I类hdac双抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-06 DOI: 10.1080/14756366.2025.2461190

Dandan Yuan, Yali Gao, Lin Xia, Han Liu, Xingye Wu, Xueyan Ding, Yudan Huang, Changchun Deng, Jin Li, Wenqi Dai, Jieqing Liu, Junjie Ma

{"title":"Discovery of novel biphenyl compounds bearing hydroxamic acid moiety as the first PD-L1/class I HDACs dual inhibitors.","authors":"Dandan Yuan, Yali Gao, Lin Xia, Han Liu, Xingye Wu, Xueyan Ding, Yudan Huang, Changchun Deng, Jin Li, Wenqi Dai, Jieqing Liu, Junjie Ma","doi":"10.1080/14756366.2025.2461190","DOIUrl":"10.1080/14756366.2025.2461190","url":null,"abstract":"Herein, we firstly reported a series of biphenyl compounds bearing hydroxamic acid moiety as PD-L1/class I HDACs dual inhibitors. Among them, compound 14 displayed the strongest inhibitory activity in vitro against HDAC2 and HDAC3 with IC50 values of 27.98 nM and 14.47 nM, and had an IC50 value of 88.10 nM for PD-1/PD-L1 interaction. Importantly, 14 could upregulate the expression of PD-L1 and CXCL10 in a PD-L1 low-expression cancer cell line (MCF-7), highlighting the potential to enhance efficacy by recruiting T-cell infiltration into TME and improving the response of PD-1/PD-L1 inhibitor associated with PD-L1 low-expression. Besides, we identified another compound, 22, which possessed the strongest inhibitory activity against PD-1/PD-L1 interaction with an IC50 value of 12.47 nM, and effectively inhibited the proliferation of three cancer cell lines. Our results suggest that compounds 14 and 22 can be served as lead compounds of PD-L1/class I HDACs dual inhibitors for further optimisation.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2461190"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy. 通过基于结构的虚拟筛选发现一种选择性PI3Kα抑制剂用于靶向结直肠癌治疗。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-24 DOI: 10.1080/14756366.2025.2468852

Hussam Albassam, Omar Almutairi, Majed Alnasser, Faisal Altowairqi, Faris Almutairi, Saad Alobid

{"title":"Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy.","authors":"Hussam Albassam, Omar Almutairi, Majed Alnasser, Faisal Altowairqi, Faris Almutairi, Saad Alobid","doi":"10.1080/14756366.2025.2468852","DOIUrl":"10.1080/14756366.2025.2468852","url":null,"abstract":"Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC50 of 12.14 µM, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019's binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2468852"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Natural product as a lead for impairing mitochondrial respiration in cancer cells. 天然产物作为损害线粒体呼吸在癌细胞中的铅。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-27 DOI: 10.1080/14756366.2025.2465575

Agnieszka Pyrczak-Felczykowska, Anna-Karina Kaczorowska, Artur Giełdoń, Alicja Braczko, Ryszard T Smoleński, Jędrzej Antosiewicz, Tristan A Reekie, Anna Herman-Antosiewicz

{"title":"Natural product as a lead for impairing mitochondrial respiration in cancer cells.","authors":"Agnieszka Pyrczak-Felczykowska, Anna-Karina Kaczorowska, Artur Giełdoń, Alicja Braczko, Ryszard T Smoleński, Jędrzej Antosiewicz, Tristan A Reekie, Anna Herman-Antosiewicz","doi":"10.1080/14756366.2025.2465575","DOIUrl":"10.1080/14756366.2025.2465575","url":null,"abstract":"The impact of the isoxazole derivative of usnic acid, ISOXUS (formerly known as 2b) on cancer and non-cancerous cell metabolism was investigated. ISOXUS significantly reduced the utilisation of most metabolic substrates that produce NADH or FADH2, mitochondrial electron flow and oxygen consumption rate (OCR) in MCF-7 breast cancer cells in contrast to HB2 normal epithelial cells. Molecular docking revealed that ISOXUS inhibits mitochondrial respiratory chain complex II, which was confirmed experimentally. Disturbance of electron flow in MCF-7 cells resulted in increased reactive oxygen species (ROS) production. They appeared crucial for ISOXUS-induced cancer cell vacuolization and a drop in survival as an antioxidant, α-tocopherol, protected against these processes. These findings indicate that ISOXUS is a metabolic inhibitor that targets mitochondrial complex II in breast cancer cells resulting in diminished ATP production and increased ROS formation which translates into reduced cell viability.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2465575"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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