Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

Discovery of a selective and reversible LSD1 inhibitor with potent anticancer effects in vitro and in vivo. 发现一种选择性和可逆性的LSD1抑制剂，在体外和体内具有有效的抗癌作用。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-20 DOI: 10.1080/14756366.2025.2466093

Xiao-Song Zhang, Jin-Zhan Liu, Ying-Ying Mei, Meng Zhang, Li-Wei Sun

{"title":"Discovery of a selective and reversible LSD1 inhibitor with potent anticancer effects in vitro and in vivo.","authors":"Xiao-Song Zhang, Jin-Zhan Liu, Ying-Ying Mei, Meng Zhang, Li-Wei Sun","doi":"10.1080/14756366.2025.2466093","DOIUrl":"10.1080/14756366.2025.2466093","url":null,"abstract":"Lysine-specific demethylase 1 (LSD1) is abnormally overexpressed in various tumour tissues of patients and has been an attractive anticancer target. In this work, a potent LSD1 inhibitor (compound 14) was designed and synthesised by the molecular hybridisation strategy. It displays the potent antiproliferative activity against HepG2, HEP3B, HUH6, and HUH7 cells with IC50 values of 0.93, 2.09, 1.43, and 4.37 μM, respectively. Furthermore, compound 14 is a selective and reversible LSD1 inhibitor with an IC50 value of 0.18 μM and increases the methylation levels of H3K4me1/2. Molecular docking studies showed that it formed hydrogen bonds, hydrophilic interactions and hydrophobic interactions with residues of LSD1. Anticancer mechanisms demonstrated that it suppresses migration and epithelial-mesenchymal transition process in HepG2 cells. Importantly, it exhibits potent anti-liver cancer effects in vivo without obvious toxic effects. These interesting findings suggested that compound 14, a novel LSD1 inhibitor, may be a promising therapeutic agent to treat liver cancer.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2466093"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458176","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

Exploring covalent inhibitors of SARS-CoV-2 main protease: from peptidomimetics to novel scaffolds. 探索SARS-CoV-2主要蛋白酶的共价抑制剂：从拟肽剂到新型支架。

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: 10.1080/14756366.2025.2460045

Noor Atatreh, Radwa E Mahgoub, Mohammad A Ghattas

引用次数: 0

Tetra-anionic porphyrin mimics protein-protein interactions between regulatory particles and the catalytic core, allosterically activating human 20S proteasome. 四阴离子卟啉模拟调节颗粒和催化核心之间的蛋白质相互作用，变构激活人20S蛋白酶体。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-04-07 DOI: 10.1080/14756366.2025.2482892

A M Santoro, M Persico, A D'Urso, A Cunsolo, O Tkachuk, D Milardi, R Purrello, G R Tundo, D Sbardella, P A Osmulski, M Gaczynska, M Coletta, C Fattorusso

{"title":"Tetra-anionic porphyrin mimics protein-protein interactions between regulatory particles and the catalytic core, allosterically activating human 20S proteasome.","authors":"A M Santoro, M Persico, A D'Urso, A Cunsolo, O Tkachuk, D Milardi, R Purrello, G R Tundo, D Sbardella, P A Osmulski, M Gaczynska, M Coletta, C Fattorusso","doi":"10.1080/14756366.2025.2482892","DOIUrl":"10.1080/14756366.2025.2482892","url":null,"abstract":"Decreased proteasome activity is a hallmark of brain and retinal neurodegenerative diseases (Alzheimer's, Parkinson's diseases, glaucoma) boosting the search for molecules acting as proteasome activators. Based on the hypothesis of an electrostatic key code driving catalytic core particle (20S) activation by regulatory particles (RPs), we identified the tetra-anionic meso-Tetrakis(4-sulphonatophenyl)-porphyrin (H2TPPS) as a new activator of human proteasome. By means of an integrated approach, including bioinformatics, enzymatic kinetic analysis, atomic force microscopy, and dynamic docking simulations, we show how binding of H2TPPS affects the closed/open conformational equilibrium of human 20S to ultimately promote substrate gate opening and proteolytic activity. These outcomes support our hypothesis and pave the way to the rational discovery of new proteasome allosteric modulators able to reproduce the key structural elements of regulatory particles responsible for catalytic activation.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2482892"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795566","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

Synthesis, in vitro and in silico studies of a novel chrysin-ferrocene Schiff base with potent anticancer activity via G1 arrest, caspase-dependent apoptosis and inhibition of topoisomerase II. 新型菊花-二茂铁希夫碱的合成、体外和硅片研究通过G1阻滞、半胱天冬酶依赖的细胞凋亡和拓扑异构酶II的抑制具有有效的抗癌活性。

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: 10.1080/14756366.2025.2501377

Mohammed Khaled Bin Break, Siddique Akber Ansari, Ahmed A Katamesh, Najah Albadari, Maali D Alshammari, Hamad M Alkahtani

{"title":"Synthesis, in vitro and in silico studies of a novel chrysin-ferrocene Schiff base with potent anticancer activity via G1 arrest, caspase-dependent apoptosis and inhibition of topoisomerase II.","authors":"Mohammed Khaled Bin Break, Siddique Akber Ansari, Ahmed A Katamesh, Najah Albadari, Maali D Alshammari, Hamad M Alkahtani","doi":"10.1080/14756366.2025.2501377","DOIUrl":"10.1080/14756366.2025.2501377","url":null,"abstract":"A novel chrysin-ferrocene Schiff base (CFSB) was synthesised as a potential anticancer agent. CFSB demonstrated high cytotoxicity against cancer cells with HepG2 (liver) being the most susceptible (IC50 = 3.11 µM). The compound was less toxic towards normal MRC5 cells and exhibited ∼5-fold selectivity towards most cancer cells. CFSB caused G1-phase arrest, induced caspase-dependent apoptosis by increasing Bax/Bcl2 ratio and reduced metastasis by decreasing MMP9 in HepG2. Furthermore, CFSB was inactive against CDK2, EGFR, TrkA and VEGFR, but it strongly inhibited topoisomerase II (IC50 = 20 µM) with potency comparable to etoposide (IC50 = 15 µM), while weak inhibition was observed against tubulin (IC50 = 76 µM). DFT calculations revealed that CFSB had desirable reactivity, while docking indicated high binding affinity with topoisomerase II. Molecular dynamics and MM-GBSA analyses showed that CFSB-topoisomerase II complex was stable with favourable binding energies, while in silico ADMET studies showed drug-like properties for CFSB.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2501377"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110485","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 sennoside B disrupts liquid-liquid phase separation of SARS-CoV-2 nucleocapsid protein by inhibiting its RNA-binding activity. 天然产物sennoside B通过抑制SARS-CoV-2核衣壳蛋白的rna结合活性，破坏其液-液相分离。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-05-15 DOI: 10.1080/14756366.2025.2501743

Da-Wei Zhang, Xiao-Shuang Xu, Liangxu Xie, Lei Xu, Zhiguo Fu, Yimin Li, Xiaojun Xu

{"title":"Natural product sennoside B disrupts liquid-liquid phase separation of SARS-CoV-2 nucleocapsid protein by inhibiting its RNA-binding activity.","authors":"Da-Wei Zhang, Xiao-Shuang Xu, Liangxu Xie, Lei Xu, Zhiguo Fu, Yimin Li, Xiaojun Xu","doi":"10.1080/14756366.2025.2501743","DOIUrl":"10.1080/14756366.2025.2501743","url":null,"abstract":"The nucleocapsid protein (NP) of SARS-CoV-2, an RNA-binding protein, is capable of undergoing liquid-liquid phase separation (LLPS) during viral infection, which plays a crucial role in virus assembly, replication, and immune regulation. In this study, we developed a homogeneous time-resolved fluorescence (HTRF) method for identifying inhibitors of the SARS-CoV-2 NP-RNA interaction. Using this HTRF-based approach, we identified two natural products, sennoside A and sennoside B, as effective blockers of this interaction. Bio-layer interferometry assays confirmed that both sennosides directly bind to the NP, with binding sites located within the C-terminal domain. Additionally, fluorescence recovery after photobleaching (FRAP) experiments revealed that sennoside B significantly inhibited RNA-induced LLPS of the NP, while sennoside A displayed comparatively weaker activity. Thus, the developed HTRF-based assay is a valuable tool for identifying novel compounds that disrupt the RNA-binding activity and LLPS of the SARS-CoV-2 NP. Our findings may facilitate the development of antiviral drugs targeting SARS-CoV-2 NP.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2501743"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078339","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

Statement of Retraction: Dependence on linkers' flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents. 撤回声明：依赖于为苯磺酰胺设计的连接体的灵活性，发现新的hCA IX抑制剂作为有效的抗癌药物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-04 DOI: 10.1080/14756366.2025.2511543

引用次数: 0

Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors. 新型5-乙基磺酰基吲哚-3-碳腙类EGFR/VEGFR-2激酶抑制剂的设计、合成和抗增殖活性

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-24 DOI: 10.1080/14756366.2025.2516075

Lamya H Al-Wahaibi, Hesham A Abou-Zied, Mohamed A Mahmoud, Bahaa G M Youssif, Stefan Bräse, Safwat M Rabea

{"title":"Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors.","authors":"Lamya H Al-Wahaibi, Hesham A Abou-Zied, Mohamed A Mahmoud, Bahaa G M Youssif, Stefan Bräse, Safwat M Rabea","doi":"10.1080/14756366.2025.2516075","DOIUrl":"https://doi.org/10.1080/14756366.2025.2516075","url":null,"abstract":"A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a-o, serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds 7a-o were assessed against four cancer cell lines via the MTT assay. Compounds 7g, 7i-7l, and 7o emerged as the most efficient six derivatives, with GI50 values ranging from 25 nM to 42 nM. Compounds 7j, 7k, and 7o (GI50 values of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI50 value of 33 nM), particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these new compounds. Computational analyses, encompassing molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) computations, elucidated the binding interactions of these drugs with EGFR and VEGFR-2.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2516075"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484656","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 of bis-thiourea derivatives as potent tyrosinase inhibitors: combined experimental and computational study. 发现双硫脲衍生物作为有效的酪氨酸酶抑制剂：结合实验和计算研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-24 DOI: 10.1080/14756366.2025.2518195

Sahachai Sabuakham, Sutita Nasoontorn, Napat Nuramrum, Atit Silsirivanit, Thanyada Rungrotmongkol, Ratchanok Pingaew, Panupong Mahalapbutr

{"title":"Discovery of bis-thiourea derivatives as potent tyrosinase inhibitors: combined experimental and computational study.","authors":"Sahachai Sabuakham, Sutita Nasoontorn, Napat Nuramrum, Atit Silsirivanit, Thanyada Rungrotmongkol, Ratchanok Pingaew, Panupong Mahalapbutr","doi":"10.1080/14756366.2025.2518195","DOIUrl":"https://doi.org/10.1080/14756366.2025.2518195","url":null,"abstract":"Tyrosinase, a key enzyme in melanin synthesis, serves as a primary target for developing depigmenting agents. The search for novel tyrosinase inhibitors is needed due to the adverse effects of current inhibitors. This study evaluated 16 bis-thiourea derivatives using in vitro and in silico methods, identifying compound 4, with chlorine substituents, as the most potent inhibitor. Compound 4 outperformed kojic acid in inhibiting mushroom tyrosinase activity and interacted with catalytic copper ions and active site residues, as revealed by molecular docking and copper-chelating assay. Molecular dynamics simulation and MM/PBSA-based free energy calculations confirmed the greater stability and binding affinity of the compound 4-tyrosinase complex in an aqueous environment compared to kojic acid-tyrosinase complex. Melanin assay revealed that compound 4 significantly suppressed melanin production in B16F10 melanoma cells, showing stronger anti-melanogenic activity than kojic acid. Drug-likeness predictions confirmed its compliance with Lipinski's rule of five, supporting bis-thiourea derivatives as promising tyrosinase inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2518195"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484657","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

Fourth-generation EGFR-TKI to overcome C797S mutation: past, present, and future. 第四代EGFR-TKI克服C797S突变：过去，现在和未来

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-04-02 DOI: 10.1080/14756366.2025.2481392

Die Zhang, Jumei Zhao, Yue Yang, Qiangfang Dai, Ning Zhang, Zhikuan Mi, Qianqian Hu, Xiaolong Liu

{"title":"Fourth-generation EGFR-TKI to overcome C797S mutation: past, present, and future.","authors":"Die Zhang, Jumei Zhao, Yue Yang, Qiangfang Dai, Ning Zhang, Zhikuan Mi, Qianqian Hu, Xiaolong Liu","doi":"10.1080/14756366.2025.2481392","DOIUrl":"10.1080/14756366.2025.2481392","url":null,"abstract":"Overactivation of the epidermal growth factor receptor (EGFR) is prevalent in various tumours, rendering it a promising target for cancer therapy, particularly in the treatment of non-small cell lung cancer (NSCLC). Although the first through third generations of EGFR tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy, the emergence of drug resistance continues to pose a challenge. Current research is now focused on fourth-generation EGFR-TKIs, which specifically target the EGFR harbouring the C797S mutation. This review examines the design strategies, antitumor activity both in vivo and in vitro, binding modes, pharmacokinetics, as well as the advantages and disadvantages of each inhibitor, alongside the progress of clinical stage research related to fourth-generation inhibitors. Additionally, the review discusses future development directions for fourth-generation EGFR-TKIs, aiming to provide insights for successful research and development in this field.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2481392"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764182","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

Synergistic optimizations of efficacy and membrane permeability of IRAK4 inhibitors: identifying new lead compounds for anti-inflammatory therapeutics. IRAK4抑制剂疗效和膜通透性的协同优化：确定抗炎治疗的新先导化合物

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-19 DOI: 10.1080/14756366.2025.2518491

Kewon Kim, Ahyoung Jang, Hyeonsoo Han, Taeho Kim, Hwangseo Park, Sungwoo Hong

{"title":"Synergistic optimizations of efficacy and membrane permeability of IRAK4 inhibitors: identifying new lead compounds for anti-inflammatory therapeutics.","authors":"Kewon Kim, Ahyoung Jang, Hyeonsoo Han, Taeho Kim, Hwangseo Park, Sungwoo Hong","doi":"10.1080/14756366.2025.2518491","DOIUrl":"10.1080/14756366.2025.2518491","url":null,"abstract":"Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and autoimmune diseases. We initiated a drug discovery campaign based on the N2,N4-diphenylpyrimidine-2,4-diamine (DPDA) scaffold, employing an integrated strategy that combined structure-based de novo design, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and biochemical evaluation. This approach emphasised the optimisation of membrane permeability by controlling the 1-octanol/water partition coefficient (LogP), while also enforcing configurational constraints to enhance IRAK4-specific binding. Through iterative cycles of computational modelling and chemical synthesis, we identified 10 out of 17 newly synthesised compounds that exhibited potent IRAK4 inhibition at low-nanomolar concentrations in both enzymatic and cellular assays. Among these, compounds 10 and 13 stood out, demonstrating strong IRAK4 inhibitory activity, favourable membrane permeability, and minimal off-target kinase interactions.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2518491"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325934","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