Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

{"title":"Expression of Concern.","authors":"","doi":"10.1080/14756366.2026.2648252","DOIUrl":"10.1080/14756366.2026.2648252","url":null,"abstract":"","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2648252"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147772964","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}

{"title":"2<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidin-4-amine derivatives as novel selective fibroblast growth factor receptor 2 (FGFR2) inhibitors.","authors":"Pinglian Wu, Zhaodi Tian, Weizhong Shen, Qiuju Xun, Yuan Tian, Huiqiong Li, Bowen Yang, Shaohua Chang, Weixue Huang, Zhen Wang, Ke Ding, Dawei Ma","doi":"10.1080/14756366.2026.2647526","DOIUrl":"10.1080/14756366.2026.2647526","url":null,"abstract":"<p><p>Although FGFR2 is a well-validated oncogenic target, no selective FGFR2 inhibitors have been approved for clinical use. In this study, we report the discovery of 2<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidin-4-amine derivative as novel, irreversible FGFR2 inhibitors. The optimal compound, <b>PLW559</b>, potently inhibited FGFR2 with an IC₅₀ value of 13.59 nM and demonstrated exceptional selectivity over FGFR1, FGFR3, and FGFR4. Covalent binding to the target was confirmed by mass spectrometry. In cellular models, <b>PLW559</b> exhibited potent and selective antiproliferative effects against FGFR2-driven cancer cells, effectively suppressed downstream FGFR2 signalling and induced cancer cell apoptosis. Notably, it showed minimal activity in non-FGFR2-dependent cells. This work presents a new class of selective FGFR2 inhibitors based on a novel scaffold, offering promising lead compounds for the development of FGFR2-target therapies.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2647526"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13037149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574055","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}

{"title":"Discovery of 2-phenylethyl chromones as potent and selective CYP1B1 inhibitors.","authors":"Wenming Chen, Wenchong Ye, Yinghong Long, Ye Zhang, Wen Zhou, Wei Wang","doi":"10.1080/14756366.2025.2598738","DOIUrl":"10.1080/14756366.2025.2598738","url":null,"abstract":"<p><p>Cytochrome P4501B1 (CYP1B1), overexpressed in solid tumours but minimally in healthy tissues, is a promising anticancer target linked to chemoresistance. While CYP1B1 inhibitors can restore drug efficacy, most suffer from limited scaffold diversity and poor selectivity against other CYPs. We identified 2-(2-phenylethyl) chromones as a novel scaffold for anti-CYP1B1 activity and synthesised 24 derivatives with varied ring A/B substituents and established the SAR. Three compounds (<b>CX-6</b>, <b>CX-9</b>, <b>CX-22</b>) showed nanomolar anti-CYP1B1 activity and exceptional selectivity (SI > 230). In CYP1B1-overexpressing cells, the water-soluble and non-cytotoxic <b>CX-9</b> (solubility > 100 μM) dose-dependently reversed docetaxel resistance, achieving efficacy at 50 μM comparable to 20 μM of the CYP1B1 inhibitor α-naphthoflavone (ANF). Molecular docking revealed similar binding modes for <b>CX-9</b> and ANF in CYP1B1's active site. This work hints 2-(2-phenylethyl) chromones as a natural-derived scaffold for promising CYP1B1 inhibitor development.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2598738"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12777840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889370","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}

{"title":"Imidazole-2-thione derivatives as new selective anticancer agents with anti-metastatic properties: synthesis and pharmacological evaluation.","authors":"Božena Golcienė, Natalia Maciejewska, Anoop Kallingal, Birutė Sapijanskaitė-Banevič, Maryna Stasevych, Vytautas Mickevičius","doi":"10.1080/14756366.2025.2607820","DOIUrl":"10.1080/14756366.2025.2607820","url":null,"abstract":"<p><p>Imidazole scaffolds are attractive in drug design for bioactivity and synthetic accessibility. We developed S-substituted imidazole-2-thione derivatives, focusing on compound <b>24</b>, which showed potent cytotoxicity against lung, cervical, and colorectal cancer cells with submicromolar IC₅₀ and selectivity over fibroblasts. Mechanistic analyses revealed G1 arrest, caspase-dependent apoptosis, and p-γH2AX accumulation. Importantly, compound <b>24</b> strongly inhibited A-549 cell migration and invasion in both 2D and 3D assays, correlating with downregulation of MMP-2, MMP-9, and hTERT. In vitro enzyme assays further confirmed that compound <b>24</b> directly inhibits MMP-9 activity. In vivo, <b>24</b> suppressed tumour growth and vasculotropic spread in the CAM model without detectable toxicity. Docking and dynamics simulations confirmed stable binding to MMP-2 and MMP-9 active sites. These results identify compound <b>24</b> as a promising anticancer agent with both cytotoxic and anti-metastatic properties, supporting its further preclinical investigation.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2607820"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12777803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911914","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}

{"title":"Design, synthesis and anti-breast cancer activity evaluation of 6,7-dihydro-5<i>H</i>-pyrrolo[3,4-<i>d</i>]pyrimidine-based PARP1/ATR dual inhibitors.","authors":"Meng-Lan He, Zong-Hao Wang, Xia Yao, Lu-Lu Ye, Bo-Qun Du, Chen-Chen Wang, Yong-Hao Chen, Xiao-Xian Wang, Hui Luo, Yuan Gao, Xiang-Yang Ye","doi":"10.1080/14756366.2026.2627053","DOIUrl":"10.1080/14756366.2026.2627053","url":null,"abstract":"<p><p>PARP1 inhibitors are FDA-approved for BRCA1/2-mutated breast cancer but show limited efficacy in wild-type cancers and face resistance issues. To overcome these, we designed novel 6,7-dihydro-5<i>H</i>-pyrrolo[3,4-<i>d</i>]pyrimidine-based compounds integrating PARP1 inhibitor pharmacophores with the ATR inhibitor AZD6738 scaffold. Substituent modifications influenced PARP1 and ATR selectivity, yielding dual inhibitors or selective PARP1 inhibitors. Compound <b>38a</b>, the lead candidate, exhibited potent dual inhibition (IC₅₀ < 20 nM) and strong antitumor effects in MDA-MB-231 (IC₅₀ < 0.048 μM) and MDA-MB-468 (IC₅₀: 0.01 μM) cell lines <i>in vitro</i>. Mechanistically, <b>38a</b> arrested cell cycle progression, induced apoptosis, inhibited colony formation and migration, and suppressed DNA damage repair pathways, outperforming combined Niraparib and AZD6738. These findings underscore the therapeutic potential of PARP1/ATR dual inhibitors for breast cancer and support further investigation.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2627053"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201805","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}

{"title":"Palladium-catalysed synthesis of small-molecule epigenetic inhibitors as anticancer therapeutics.","authors":"Ram Sharma, Mandeep Rana, Amandeep Thakur, Ritu Ojha, Seyyed Mojtaba Mousavi, Ashwani Dhingra, Kunal Nepali","doi":"10.1080/14756366.2026.2621477","DOIUrl":"10.1080/14756366.2026.2621477","url":null,"abstract":"<p><p>Palladium-catalysed reactions have emerged as indispensable tools in medicinal chemistry, enabling the precise construction of C-C and C-N bonds across a wide spectrum of drug-like molecular frameworks. This manuscript comprehensively examines advances reported over the past five years in palladium-catalysed methodologies applied to epigenetic drug discovery. The mechanistic diversity and synthetic adaptability of palladium catalysts for accessing scaffolds addressing the epigenetic targets have been highlighted. The robust drug design strategies and activity profile of the generated small molecule epigenetic inhibitors through palladium-assisted synthetic protocol are also presented in this compilation. Particular emphasis is placed on understanding the influence of ligand structure, base selection, and solvent optimisation in modulating catalyst reactivity. Collectively, this review offers a practical and forward-looking framework for the design and synthesis of next-generation epigenetic anticancer therapeutics (selective/non-selective/hybrid-inhibitors and degraders/PROTACS).</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2621477"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201849","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}

{"title":"Insights into the complexity of SARS-CoV-2 M^pro inhibition: Ebselen and its derivatives impair dimerisation of the enzyme.","authors":"Simone Fabbian, Silvia Fabi, Laurin Schwarz, Giovanni Preto, Chiara Schiavinato, Cristiano Salata, Letizia Crocetti, Roberto Battistutta, Barbara Gatto, Alice Sosic","doi":"10.1080/14756366.2025.2604232","DOIUrl":"10.1080/14756366.2025.2604232","url":null,"abstract":"<p><p>The SARS-CoV-2 Main Protease (M^pro), a key enzyme for viral replication, represents a highly attractive target for the development of broad-spectrum anti-coronavirus therapeutics. The organoselenium drug Ebselen has shown potent <i>in vitro</i> inhibition of M^pro as well as antiviral activity, granting clinical interest as a COVID-19 treatment option. Here we show that Ebselen and selected derivatives with human neutrophil elastase (HNE) inhibition and anti-radical activity are able to bind covalently to the viral enzyme with multiple stoichiometry, exhibiting inhibitory activity towards SARS-CoV-2 M^pro with potencies in the nanomolar range. Employing a mass spectrometry-based approach, we show that, upon binding to the target, Ebselen and its derivatives induce a dose-dependent shift in the dimer-monomer equilibrium, favouring the inactive monomeric state of the viral protease and possibly contributing to the observed <i>in vitro</i> inhibition.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2604232"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12777896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892546","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}

{"title":"Discovery of novel N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives as MAO-B inhibitors for the treatment of Parkinson's disease.","authors":"Ziwei Wang, Jing Feng, Chengwan Yi, Wanping Zhang, Xianwu Fu, Yu Yu","doi":"10.1080/14756366.2025.2606434","DOIUrl":"10.1080/14756366.2025.2606434","url":null,"abstract":"<p><p>Monoamine oxidase B (MAO-B) inhibitors may be an effective therapeutic approach for Parkinson's disease. This study designed and synthesised a series of N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives and evaluated their inhibitory activity against human MAO-B (hMAO-B). Most compounds exhibited inhibitory activity and selectivity, with compounds <b>29</b> and <b>34 </b>demonstrating the strongest inhibitory potency (IC₅₀ = 0.066 ± 0.03 μM and 0.070 ± 0.002 μM, respectively) and selectivity indices (SI > 151 and 134), which were superior to the positive control rasagiline. Enzyme kinetic studies confirmed that these representative active compounds exhibited mixed reversible inhibition of hMAO-B. Molecular docking and kinetic analyses indicated that compound <b>29</b> binds stably to the hMAO-B active site. Concurrently, they exhibited low neurotoxicity and protective effects against 6-OHDA-induced damage in SH-SY5Y neuroblastoma cells. Therefore, we propose these active compounds as potential drug candidates for further investigation.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2606434"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933583","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}

{"title":"Investigation of exercise-mimetic bioactive molecules as modulators of MMP activity and expression in cancer cells.","authors":"Ha Vy Thi Vo, Geewoo Nam Patton, Jae Sung Park, Song Ja Kim, Namdoo Kim, Hyuck Jin Lee","doi":"10.1080/14756366.2026.2616019","DOIUrl":"10.1080/14756366.2026.2616019","url":null,"abstract":"<p><p>Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are directly involved in the degradation of the extracellular matrix preceding uncontrolled cancer growth and metastasis. For these reasons, MMPs are considered key therapeutic targets in the development of cancer treatments. Acknowledged for its prophylactic effects against various diseases including cancer, physical exercise has been reported to boost the immune system, enhance endogenous defence mechanisms, manage oxidative stress, and regulate MMP. Despite its benefits, patients with compromised capacity for physical activity due to injuries and frailty are often unable to take advantage of them. As a possible solution for this problem, the alternative therapeutic approach of exercise mimetics has been gaining traction through pharmacological interventions. Exercise mimetics are pharmacological agents that partially mimic the molecular and physiological benefits of physical exercise without requiring actual physical activity. Recent studies have indicated that the potential of these compounds may serve as candidates for further investigation in cancer treatment. In this study, the possible anti-cancer and anti-metastatic-related effects of six selected exercise mimetics (<i>i.e</i>., <b>AICAR</b>, <b>Icariin</b>, <b>Berberine</b>, <b>Betaine</b>, <b>GW501516</b>, and <b>Metformin</b>) were investigated by targeting activity and/or expression of MMP-2/9 in <i>in vitro</i> model. These compounds (i) inhibited MMP-2 activity by interacting with the active site and/or allosteric sites, (ii) downregulated MMP-2/9 expression by influencing STAT3 signalling pathways, and (iii) reduced lung cancer cells (A549) viability to varying degrees. Among the exercise mimetics, Icariin and Berberine have relatively stronger effects on both the activity of MMP-2 and the expression of MMP-2/9 in cancer cells. These findings highlight the novel potential of exercise mimetics as targeted cancer therapeutics through the regulation of MMP activity and expression in cancer progression and metastasis.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2616019"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12821374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003477","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}

{"title":"Design and optimisation of meta-substituted bis(arylsulfonamido)benzene inhibitors through a molecular hybridisation strategy targeting the Keap1-Nrf2 protein-protein interaction.","authors":"Sumi Lee, Ahmed R Ali, Dhulfiqar Ali Abed, Longqin Hu","doi":"10.1080/14756366.2026.2622777","DOIUrl":"10.1080/14756366.2026.2622777","url":null,"abstract":"<p><p>Nrf2 is recognised as an attractive therapeutic target for oxidative stress-related disorders through its regulation of antioxidant gene transcription. Direct inhibition of Keap1-Nrf2 protein-protein interaction represents a promising strategy to modulate Nrf2 activity. Herein, we report the discovery of meta-substituted bis(arylsulfonamido)benzene derivatives using a molecular hybridisation strategy based onpotent inhibitors <b>2a</b> and <b>3a</b>. Among the initial hybrids, <b>7a</b> demonstrated good potency in the FP assay, making it a suitable lead for SAR optimisation. Our study found <b>13b</b> was the most potent analog, showing IC₅₀ values of 183.4 nM in the FP assay and 107.5 nM in the TR-FRET assay. It also demonstrated excellent metabolic stability, with 93.9% remaining after a 30 minute-incubation in human liver microsomes. Collectively, these results highlight <b>13b</b> as a non-covalent Keap1-Nrf2PPI inhibitor, with balanced potency and metabolic stability, supporting its potential as a tractable scaffold for further optimisation to modulate the Nrf2 pathway.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2622777"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12885012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125092","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}