Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第6页

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

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

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