Miriana Di Stefano, Salvatore Galati, Lisa Piazza, Francesca Gado, Carlotta Granchi, Marco Macchia, Antonio Giordano, Tiziano Tuccinardi, Giulio Poli
{"title":"Watermelon: setup and validation of an <i>in silico</i> fragment-based approach.","authors":"Miriana Di Stefano, Salvatore Galati, Lisa Piazza, Francesca Gado, Carlotta Granchi, Marco Macchia, Antonio Giordano, Tiziano Tuccinardi, Giulio Poli","doi":"10.1080/14756366.2024.2356179","DOIUrl":"10.1080/14756366.2024.2356179","url":null,"abstract":"<p><p>We present a new computational approach, named <i>Watermelon</i>, designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target's binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the <i>Watermelon</i> approach.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2356179"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306106","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}
Mohamed Elagawany, Lina M A Abdel Ghany, Tarek S Ibrahim, Abdulrhman S Alharbi, Mohamed S Abdel-Aziz, Eman M El-Labbad, Noha Ryad
{"title":"Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kβ kinases.","authors":"Mohamed Elagawany, Lina M A Abdel Ghany, Tarek S Ibrahim, Abdulrhman S Alharbi, Mohamed S Abdel-Aziz, Eman M El-Labbad, Noha Ryad","doi":"10.1080/14756366.2024.2311157","DOIUrl":"10.1080/14756366.2024.2311157","url":null,"abstract":"<p><p>Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds <b>5</b>, <b>4b</b>, and <b>4a</b> possessed potent cytotoxic activity against PC-3 cells with IC<sub>50</sub> 3.56, 8.99, and 10.22 µM, respectively. Compound <b>4c</b> displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC<sub>50</sub> 8.5 µM. Moreover, compound <b>5</b> exhibited potent inhibitory activity on EFGR with IC<sub>50</sub> 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity. Docking aligns with the <i>in vitro</i> results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound <b>5</b> decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound <b>5</b> caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2311157"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722893","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 and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation.","authors":"Xiao Qiao, Xiangyu Wu, Shutong Chen, Miao-Miao Niu, Huilian Hua, Yan Zhang","doi":"10.1080/14756366.2023.2295241","DOIUrl":"10.1080/14756366.2023.2295241","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant <i>in vivo</i> antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2295241"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885025","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}
Md Habibur Rahaman, Sara J Thygesen, Michael J Maxwell, Hyoyoung Kim, Prerna Mudai, Jeffrey D Nanson, Xinying Jia, Parimala R Vajjhala, Andrew Hedger, Irina Vetter, Thomas Haselhorst, Avril A B Robertson, Brian Dymock, Thomas Ve, Mehdi Mobli, Katryn J Stacey, Bostjan Kobe
{"title":"o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2.","authors":"Md Habibur Rahaman, Sara J Thygesen, Michael J Maxwell, Hyoyoung Kim, Prerna Mudai, Jeffrey D Nanson, Xinying Jia, Parimala R Vajjhala, Andrew Hedger, Irina Vetter, Thomas Haselhorst, Avril A B Robertson, Brian Dymock, Thomas Ve, Mehdi Mobli, Katryn J Stacey, Bostjan Kobe","doi":"10.1080/14756366.2024.2313055","DOIUrl":"10.1080/14756366.2024.2313055","url":null,"abstract":"<p><p>Toll-like receptor (TLR) innate immunity signalling protects against pathogens, but excessive or prolonged signalling contributes to a range of inflammatory conditions. Structural information on the TLR cytoplasmic TIR (Toll/interleukin-1 receptor) domains and the downstream adaptor proteins can help us develop inhibitors targeting this pathway. The small molecule o-vanillin has previously been reported as an inhibitor of TLR2 signalling. To study its mechanism of action, we tested its binding to the TIR domain of the TLR adaptor MAL/TIRAP (MAL<sup>TIR</sup>). We show that o-vanillin binds to MAL<sup>TIR</sup> and inhibits its higher-order assembly <i>in vitro</i>. Using NMR approaches, we show that o-vanillin forms a covalent bond with lysine 210 of MAL. We confirm in mouse and human cells that o-vanillin inhibits TLR2 but not TLR4 signalling, independently of MAL, suggesting it may covalently modify TLR2 signalling complexes directly. Reactive aldehyde-containing small molecules such as o-vanillin may target multiple proteins in the cell.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2313055"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990277","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}
Juan Carlos García-Soriano, Héctor de Lucio, Daniel Elvira-Blázquez, Mercedes Alcón-Calderón, Natalia Sanz Del Olmo, Pedro A Sánchez-Murcia, Paula Ortega, Francisco Javier de la Mata, Antonio Jiménez-Ruiz
{"title":"The repertoire of iron superoxide dismutases from <i>Leishmania infantum</i> as targets in the search for therapeutic agents against leishmaniasis.","authors":"Juan Carlos García-Soriano, Héctor de Lucio, Daniel Elvira-Blázquez, Mercedes Alcón-Calderón, Natalia Sanz Del Olmo, Pedro A Sánchez-Murcia, Paula Ortega, Francisco Javier de la Mata, Antonio Jiménez-Ruiz","doi":"10.1080/14756366.2024.2377586","DOIUrl":"10.1080/14756366.2024.2377586","url":null,"abstract":"<p><p>Species of <i>Leishmania</i> and <i>Trypanosoma</i> genera are the causative agents of relevant parasitic diseases. Survival inside their hosts requires the existence of a potent antioxidant enzymatic machinery. Four iron superoxide dismutases have been described in trypanosomatids (FeSODA, FeSODB1, FeSODB2, and FeSODC) that hold a potential as therapeutic targets. Nonetheless, very few studies have been developed that make use of the purified enzymes. Moreover, FeSODC remains uncharacterised in <i>Leishmania</i>. In this work, for the first time, we describe the purification and enzymatic activity of recombinant versions of the four <i>Leishmania</i> FeSOD isoforms and establish an improved strategy for developing inhibitors. We propose a novel parameter [(<i>V</i>*<sub>cyt. c</sub> - <i>V</i><sub>cyt. c</sub>)/<i>V</i><sub>cyt. c</sub>] which, in contrast to that used in the classical cytochrome c reduction assay, correlates linearly with enzyme concentration. As a proof of concept, we determine the IC<sub>50</sub> values of two ruthenium carbosilane metallodendrimers against these isoforms.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2377586"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734333","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 anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.","authors":"Kang-Li Wang, Tsung-Yu Yeh, Pei-Chen Hsu, Tzu-Hsuan Wong, Jia-Rong Liu, Ji-Wang Chern, Miao-Hsia Lin, Chao-Wu Yu","doi":"10.1080/14756366.2024.2318645","DOIUrl":"10.1080/14756366.2024.2318645","url":null,"abstract":"<p><p>A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound <b>3b</b>, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC<sub>50</sub> = 16 nM and 1.03 µM, respectively). Compound <b>3b</b> also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC<sub>50</sub>, 4.9 nM). Moreover, <b>3b</b> inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers <i>in vivo</i>, <b>3b</b> was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, <b>3b</b> inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2318645"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10930102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140094175","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}
Leyuan Chen, Zhonghao Ren, Yunze Zhang, Wenbin Hou, Yiliang Li
{"title":"Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells.","authors":"Leyuan Chen, Zhonghao Ren, Yunze Zhang, Wenbin Hou, Yiliang Li","doi":"10.1080/14756366.2024.2383886","DOIUrl":"10.1080/14756366.2024.2383886","url":null,"abstract":"<p><p>Specifically inducing the degradation of acidic nucleoplasmic DNA-binding protein 1 (And1) is a promising antitumor strategy. Our previous study identified Bazedoxifene (BZA) and CH3 as specific And1 degraders and validated their activity in reversing radiotherapy resistance <i>in vitro</i> and <i>in vivo</i>. However, unelucidated structure-activity relationships and moderate activity have limited their application. In this study, 27 novel CH3 derivatives were designed and synthesised based on the cavity topology of the WD40 domain of And1. Among them, <b>A15</b> with a \"V\" conformation significantly induced And1 degradation in NSCLC cells. In addition, this study demonstrated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors. 1 µM of Olaparib in combination with 5 µM of <b>A15</b> significantly inhibited the proliferation of A549 and H460 cells. Overall, these compounds are valuable tools for elucidating And1 biology, and their special spatial conformation make them promising candidates for future optimisation studies.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2383886"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788224","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}
Liuzeng Chen, Ke Wang, Xiaohan Liu, Lifan Wang, Hui Zou, Shuying Hu, Lingling Zhou, Rong Li, Shiying Cao, Banfeng Ruan, Quanren Cui
{"title":"Design, synthesis, <i>in vitro</i> and <i>in vivo</i> biological evaluation of pterostilbene derivatives for anti-inflammation therapy.","authors":"Liuzeng Chen, Ke Wang, Xiaohan Liu, Lifan Wang, Hui Zou, Shuying Hu, Lingling Zhou, Rong Li, Shiying Cao, Banfeng Ruan, Quanren Cui","doi":"10.1080/14756366.2024.2315227","DOIUrl":"10.1080/14756366.2024.2315227","url":null,"abstract":"<p><p>Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound <b>E2</b> was the most active (against NO: IC<sub>50</sub> = 0.7 μM) than celecoxib. Further studies showed that compound <b>E2</b> exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. <i>In vivo</i> experiments revealed that compound <b>E2</b> had a good alleviating effect on acute colitis in mice. In conclusion, compound <b>E2</b> may be a promising anti-inflammatory lead compound.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2315227"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10906133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990276","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}
Jiří Řehulka, Michal Jurášek, Pavel Dráber, Aleksandra Ivanová, Soňa Gurská, Kateřina Ječmeňová, Olena Mokshyna, Marián Hajdúch, Pavel Polishchuk, Pavel B Drašar, Petr Džubák
{"title":"Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation.","authors":"Jiří Řehulka, Michal Jurášek, Pavel Dráber, Aleksandra Ivanová, Soňa Gurská, Kateřina Ječmeňová, Olena Mokshyna, Marián Hajdúch, Pavel Polishchuk, Pavel B Drašar, Petr Džubák","doi":"10.1080/14756366.2024.2367139","DOIUrl":"10.1080/14756366.2024.2367139","url":null,"abstract":"<p><p>Estradiol dimers (EDs) possess significant anticancer activity by targeting tubulin dynamics. In this study, we synthesised 12 EDs variants via copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction, focusing on structural modifications within the aromatic bridge connecting two estradiol moieties. <i>In vitro</i> testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC<sub>50</sub> = 0.38 μM in CCRF-CEM) and ED5 (IC<sub>50</sub> = 0.71 μM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC<sub>50</sub> = 1.61 μM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and <i>in vitro</i> assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an <i>in silico</i> model illustrating the probable binding modes of ED3 and ED5, suggesting that dimers with a simple linker and a single substituent on the aromatic central ring possess enhanced characteristics compared to more complex dimers.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2367139"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC467089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432071","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}
Hassan Gamal, Khadiga A Ismail, A-Mohsen M E Omar, Mohamed Teleb, Marwa M Abu-Serie, Sun Huang, Abdalla S Abdelsattar, Gerald W Zamponi, Hesham Fahmy
{"title":"Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.","authors":"Hassan Gamal, Khadiga A Ismail, A-Mohsen M E Omar, Mohamed Teleb, Marwa M Abu-Serie, Sun Huang, Abdalla S Abdelsattar, Gerald W Zamponi, Hesham Fahmy","doi":"10.1080/14756366.2024.2388209","DOIUrl":"10.1080/14756366.2024.2388209","url":null,"abstract":"<p><p>Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that <b>6d</b> has a balanced profile of cytotoxicity (IC<sub>50</sub> = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC<sub>50</sub> = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that <b>6d</b> synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC<sub>50</sub> by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2388209"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975776","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}