Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第9页

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

Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation. 5,6 -二氢- 8h -异喹啉[1,2 -b]喹唑啉-8- 1衍生物作为抑制巨噬细胞源性泡沫细胞形成的新型非脂源性ABCA1上调调节剂的合成和评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-26 DOI: 10.1080/14756366.2025.2470310

Changhuan Yang, Lin Chen, Yanmei Jiang, Demeng Sun, Yun Hu

{"title":"Synthesis and evaluation of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation.","authors":"Changhuan Yang, Lin Chen, Yanmei Jiang, Demeng Sun, Yun Hu","doi":"10.1080/14756366.2025.2470310","DOIUrl":"10.1080/14756366.2025.2470310","url":null,"abstract":"Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate ABCA1 expression. The structure-activity relationship was explored and summarised. Among the 28 derivatives, compound 3 exhibited the most potent activity in activating the ABCA1 promoter (2.50-fold), significantly up-regulating both ABCA1 mRNA and protein levels in RAW264.7 macrophage cells. Mechanism studies revealed that compound 3 acted by targeting the LXR-involved pathway. In a foam cell model, compound 3 reduced ox-LDL-induced lipid accumulation and thereby inhibited foam cell formation. Moreover, compared to the LXR agonist T0901317, compound 3 led to minimal accumulation of unwanted lipids and triglycerides in HepG2 cells. With little cytotoxicity towards all the tested cell lines, compound 3 holds promise as a novel potential anti-atherogenic agent for further exploration.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2470310"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501949","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

Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D. A、C和D类丝氨酸β-内酰胺酶底物结合袋的结构比较。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2024-12-23 DOI: 10.1080/14756366.2024.2435365

Hyeonmin Lee, Hyunjae Park, Kiwoong Kwak, Chae-Eun Lee, Jiwon Yun, Donghyun Lee, Jung Hun Lee, Sang Hee Lee, Lin-Woo Kang

{"title":"Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.","authors":"Hyeonmin Lee, Hyunjae Park, Kiwoong Kwak, Chae-Eun Lee, Jiwon Yun, Donghyun Lee, Jung Hun Lee, Sang Hee Lee, Lin-Woo Kang","doi":"10.1080/14756366.2024.2435365","DOIUrl":"https://doi.org/10.1080/14756366.2024.2435365","url":null,"abstract":"β-lactams have been the most successful antibiotics, but the rise of multi-drug resistant (MDR) bacteria threatens their effectiveness. Serine β-lactamases (SBLs), among the most common causes of resistance, are classified as A, C, and D, with numerous variants complicating structural and substrate spectrum comparisons. This study compares representative SBLs of these classes, focusing on the substrate-binding pocket (SBP). SBP is kidney bean-shaped on the indented surface, formed mainly by loops L1, L2, and L3, and an additional loop Lc in class C. β-lactams bind in a conserved orientation, with the β-lactam ring towards L2 and additional rings towards the space between L1 and L3. Structural comparison shows each class has distinct SBP structures, but subclasses share a conserved scaffold. The SBP structure, accommodating complimentary β-lactams, determines the substrate spectrum of SBLs. The systematic comparison of SBLs, including structural compatibility between β-lactams and SBPs, will help understand their substrate spectrum.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2435365"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877318","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 development of steroidal enzyme inhibitors as anti-cancer drugs: state-of-the-art and future perspectives. 甾体酶抑制剂作为抗癌药物的发现和发展：最新进展和未来展望。

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: 10.1080/14756366.2025.2483818

Bruno Cerra, Antimo Gioiello

{"title":"Discovery and development of steroidal enzyme inhibitors as anti-cancer drugs: state-of-the-art and future perspectives.","authors":"Bruno Cerra, Antimo Gioiello","doi":"10.1080/14756366.2025.2483818","DOIUrl":"10.1080/14756366.2025.2483818","url":null,"abstract":"Steroidal compounds have emerged as effective therapeutic agents in oncology. Beyond natural-occurring and synthetic steroids that act as cytotoxic anti-tumoral agents, steroidal derivatives can be designed to mime the endogenous substrates of key metabolic enzymes in steroidogenesis, thus reducing the circulating levels of relevant oestrogenic and androgenic hormones responsible for cancer survival and proliferation. Therefore, enzyme inhibition represents an intriguing endocrine approach for the treatment of hormone-dependent tumours, such as breast and prostate cancer, with well-known approved drugs and several pre-clinical and clinical candidates under investigation. This review summarises the key advancements over the past decade (2014-2024) in the development of steroidal enzyme inhibitors endowed with anticancer activity, illustrating their mechanisms of action, therapeutic potential, drug design approaches, and current clinical applications. Furthermore, we discuss challenges related to drug resistance, off-target effects, and future strategies to optimise their efficacy in oncology.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2483818"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764180","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

Structure-based design of new potent and highly selective PARP-1 inhibitor for treating colorectal cancer. 基于结构的新型高效、高选择性PARP-1抑制剂治疗结直肠癌的设计。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-08-12 DOI: 10.1080/14756366.2025.2542358

Chunying Jiang, Shudan Yang, Yuting Wang, Liyuan Du, Miao-Miao Niu, Dongli Zhang

引用次数: 0

Exploring structure-activity relationships of pyrrolyl diketo acid derivatives as non-nucleoside inhibitors of terminal deoxynucleotidyl transferase enzyme. 探讨吡咯酰二酮酸衍生物作为末端脱氧核苷酸转移酶非核苷类抑制剂的构效关系。

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: 10.1080/14756366.2025.2496782

Valentina Noemi Madia, Nadia Garibaldi, Davide Ialongo, Elisa Patacchini, Valeria Tudino, Giuseppe Ruggieri, Laura Zarbo, Emanuele Cara, Antonio Coluccia, Marco Artico, Luigi Scipione, Antonella Messore, Francesco Saccoliti, Elisa Mentegari, Giovanni Maga, Roberto Di Santo, Emmanuele Crespan, Roberta Costi

{"title":"Exploring structure-activity relationships of pyrrolyl diketo acid derivatives as non-nucleoside inhibitors of terminal deoxynucleotidyl transferase enzyme.","authors":"Valentina Noemi Madia, Nadia Garibaldi, Davide Ialongo, Elisa Patacchini, Valeria Tudino, Giuseppe Ruggieri, Laura Zarbo, Emanuele Cara, Antonio Coluccia, Marco Artico, Luigi Scipione, Antonella Messore, Francesco Saccoliti, Elisa Mentegari, Giovanni Maga, Roberto Di Santo, Emmanuele Crespan, Roberta Costi","doi":"10.1080/14756366.2025.2496782","DOIUrl":"10.1080/14756366.2025.2496782","url":null,"abstract":"Terminal deoxynucleotidyl transferase (TdT) is overexpressed in some cancer types, where it drives the mutagenic repair of double strand breaks through non canonical non-homologous end joining pathway. The TdT enzyme belongs to the X family of polymerases, together with the DNA polymerase λ (pol λ) and β (pol β). However, TdT exclusively displays template-independent nucleotide polymerisation. Pursuing our studies in developing TdT inhibitors, herein we deepened the structure-activity relationships of new structural analogues of our previously identified hit compounds. The diketo hexenoic acid derivatives here analysed showed high selectivity towards TdT and inhibition potencies spanning from the low micromolar range to the nanomolar. Docking studies highlighted the chemical features involved in the TdT binding, well contributing to the rationalisation of the structural requirements needed for the enzymatic inhibition.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2496782"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248222","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

Site-selective arylations of nature-inspired flavonoids or steroidal phenols via C-H or O-H activation. 通过C-H或O-H活化的天然类黄酮或甾体酚的位点选择性芳基化。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-07-18 DOI: 10.1080/14756366.2025.2530615

Rebeka Ignácz, Noémi Bózsity, Dénes Unger, Zoltán Kele, István Zupkó, Attila Hunyadi, Marija Gjorgoska, Tea Lanišnik Rižner, Erzsébet Mernyák

{"title":"Site-selective arylations of nature-inspired flavonoids or steroidal phenols via C-H or O-H activation.","authors":"Rebeka Ignácz, Noémi Bózsity, Dénes Unger, Zoltán Kele, István Zupkó, Attila Hunyadi, Marija Gjorgoska, Tea Lanišnik Rižner, Erzsébet Mernyák","doi":"10.1080/14756366.2025.2530615","DOIUrl":"10.1080/14756366.2025.2530615","url":null,"abstract":"Phenols are important structural elements of natural products and pharmaceuticals. Due to their versatile chemical transformability, phenols are frequently used building blocks in medicinal chemistry. Their aromatic nature allows directed C(sp2)-H functionalisations, especially at the ortho positions. In contrast, meta substitutions are less well known. As a continuation of our recently described metal-catalysed cross couplings, here we report arylations of two nature-inspired phenol derivatives via C-H or O-H activation. A directing group (DG) was introduced onto C-3-O of 13α-oestrone, and the resulting carbamate was subjected to Cu(II)-catalysed meta arylation using diaryliodonium triflates as reagents. As a result, C-1-arylated derivatives were obtained. The arylation of the 1'-O-butyl protoapigenone proceeded regioselectively at C-5-O. The 1-(4-tert-butylphenyl)-13α-oestrone carbamate and all O-arylated protoflavones substantially inhibited the growth of the applied human cancer cell lines and exerted proapoptotic activity on HeLa cells. The 1-(4-tert-butylphenyl)-13α-oestrone proved to be a potent 17β-HSD1 inhibitor.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2530615"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659379","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

Inhibition mechanism and behaviour of wedelolactone against α-glucosidase. 魏德内酯对α-葡萄糖苷酶的抑制机制及行为。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-09-02 DOI: 10.1080/14756366.2025.2551970

Jianjun Zhang, Min Zhao, Fan Wu, Zheng Shi, Rui Xie

引用次数: 0

Design and synthesis of polymer nanoparticles with pH-responsive pan-HDAC inhibitor (C5) derived from norbornene block copolymers to increase C5 solubility and improve its targeted delivery to prostate cancer sites. 基于降冰片烯嵌段共聚物的ph响应泛hdac抑制剂（C5）纳米聚合物的设计与合成，以提高C5的溶解度并改善其在前列腺癌部位的靶向递送。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-07-23 DOI: 10.1080/14756366.2025.2530557

Jacob Mathew, Anshul Mishra, Trong-Nghia Le, Jing-Ping Liou, Mei-Jung Lai, Vijayakameswara Rao Neralla

{"title":"Design and synthesis of polymer nanoparticles with pH-responsive pan-HDAC inhibitor (C5) derived from norbornene block copolymers to increase C5 solubility and improve its targeted delivery to prostate cancer sites.","authors":"Jacob Mathew, Anshul Mishra, Trong-Nghia Le, Jing-Ping Liou, Mei-Jung Lai, Vijayakameswara Rao Neralla","doi":"10.1080/14756366.2025.2530557","DOIUrl":"10.1080/14756366.2025.2530557","url":null,"abstract":"This study investigated the incorporation of C5, a pan-HDAC inhibitor, into a norbornene-derived block copolymer with pH-sensitive hydrolysis (PNEG-b-P(Nor-PABA-C5)) to generate NPs for prostate cancer treatment. Amphiphilic PNEG-b-P(Nor-PABA-C5) formed NPs in aqueous environments, with hydrophobic Nor-PABA-C5 monomers in the core and hydrophilic PNEG monomers on the surface. DLS analysis showed a particle size of 122 ± 12 nm with a PDI of 0.35, confirmed by SEM and TEM. TEM imaging revealed spherical morphology, enabling the NPs to transport hydrophobic pan-HDACi drugs to PC-3 tumour sites and facilitate release through hydrolysis under acidic conditions. The NPs exhibited pH-hydrolysis characteristics, with enhanced drug release (61 ± 1.7%) at pH 6.2 compared to pH 7.4 (35 ± 0.8%). MTT assay confirmed antiproliferative effect. Analysis of FITC/(PNEG-b-P(Nor-PABA-C5)) cellular uptake showed increased absorption in prostate tumours. Live/dead cell assays showed loss of viability, with increased red fluorescence and morphological disruption at higher concentrations over 48 and 72 h.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2530557"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690483","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