Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第8页

Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening. 利用高通量虚拟筛选技术鉴定靶向泛素特异性蛋白酶11 （USP11）的化学支架

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-30 DOI: 10.1080/14756366.2025.2518191

Hobin Lee, Sunghoon Hurh, Soomin Kang, Jihwan Yoon, Jong-Ik Hwang, Derek T Logan, Hong-Rae Kim

{"title":"Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening.","authors":"Hobin Lee, Sunghoon Hurh, Soomin Kang, Jihwan Yoon, Jong-Ik Hwang, Derek T Logan, Hong-Rae Kim","doi":"10.1080/14756366.2025.2518191","DOIUrl":"10.1080/14756366.2025.2518191","url":null,"abstract":"USP11 is a promising therapeutic target implicated in Alzheimer's disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2518191"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528161","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

A study of flavonoid inhibitors against Monkeypox H1 phosphatase. 猴痘H1磷酸酶类黄酮抑制剂的研究。

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: 10.1080/14756366.2025.2535585

Hwa Young Kim, Mi-Sun Kim, Dong Hae Shin

{"title":"A study of flavonoid inhibitors against Monkeypox H1 phosphatase.","authors":"Hwa Young Kim, Mi-Sun Kim, Dong Hae Shin","doi":"10.1080/14756366.2025.2535585","DOIUrl":"10.1080/14756366.2025.2535585","url":null,"abstract":"Poxviruses regulate their replication cycle through host phosphorylation pathways, with dual-specific phosphatase H1(DUSP-H1) playing a key role in immune evasion by dephosphorylating STAT1 and inhibiting interferon(IFN) responses. Given its high conservation across orthopoxviruses, it represents a promising antiviral target. This study screened a flavonoid library against DUSP-H1 from monkeypox virus (mDUSP-H1) using a malachite green-based phosphatase assay, identifying Myricetin, (-)-Gallocatechin, Cupressuflavone, (-)-Epigallocatechin gallate, Baicalein, and Herbacetin as potent mDUSP-H1 inhibitors (IC50: 7.07-14.05 μM). Docking analysis revealed key hydrogen bonding interactions between 5,7-hydroxyl groups of the hydroxyflavone backbone and Asp79 and Arg116 of mDUSP-H1, respectively. Additional interactions with Ser23 via the 3'-hydroxyl group seems to enhance binding and effectively blocking the enzyme's active site. These findings align with previous studies on tyrosine phosphatase inhibitors, supporting flavonoids as broad-spectrum viral phosphatase inhibitors. Further structural and pharmacokinetic studies will aid in developing optimised antiviral therapies against monkeypox, variola, and cowpox viruses.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2535585"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12344671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821515","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

Nucleoside diphosphate kinase strongly promotes GDP and ADP metabolism in the cell and affects endogenous proton leak in mitochondria - the kinase is hampered by oxidative phosphorylation inhibitors. 核苷二磷酸激酶强烈促进细胞内GDP和ADP代谢，并影响线粒体内源性质子泄漏-该激酶受到氧化磷酸化抑制剂的阻碍。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-07-17 DOI: 10.1080/14756366.2025.2520611

Andrzej M Woyda-Ploszczyca

{"title":"Nucleoside diphosphate kinase strongly promotes GDP and ADP metabolism in the cell and affects endogenous proton leak in mitochondria - the kinase is hampered by oxidative phosphorylation inhibitors.","authors":"Andrzej M Woyda-Ploszczyca","doi":"10.1080/14756366.2025.2520611","DOIUrl":"10.1080/14756366.2025.2520611","url":null,"abstract":"Rapid GDP metabolism in mitochondria isolated from wild-type yeast is postulated. The hallmark of exogenous GDP is convergence with the effect of exogenous ADP, typically inducing oxidative phosphorylation (OXPHOS). The GDP-provoked changes in the presence of ATP, i.e. increased respiratory rate accompanied by decreased inner mitochondrial membrane electrical potential, were curtailed by OXPHOS inhibitors, such as carboxyatractyloside, which apparently merged the GDP effect with OXPHOS. However, all performed tests indicated that the response of mitochondria to GDP is indirect and involves two steps. First, GDP is transphosphorylated via nucleoside diphosphate kinase (NDPK), ATP + GDP → ADP + GTP, which is followed by ADP-induced OXPHOS. Importantly, in mitochondria isolated from mutant yeast with a deleted NDPK gene, the stimulatory effect of GDP was eliminated. Therefore, a prerequisite for GDP metabolic action is the cooperation of NDPK with the OXPHOS apparatus. This biological model can help elucidate the molecular basis of some diseases treatment, such as cancer.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2520611"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649519","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

Myeloperoxidase as a therapeutic target for oxidative damage in Alzheimer's disease. 髓过氧化物酶作为阿尔茨海默病氧化损伤的治疗靶点。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-14 DOI: 10.1080/14756366.2025.2456282

Astrid Mayleth Rivera Antonio, Itzia Irene Padilla Martínez, Mónica A Torres-Ramos, Martha Cecilia Rosales-Hernández

{"title":"Myeloperoxidase as a therapeutic target for oxidative damage in Alzheimer's disease.","authors":"Astrid Mayleth Rivera Antonio, Itzia Irene Padilla Martínez, Mónica A Torres-Ramos, Martha Cecilia Rosales-Hernández","doi":"10.1080/14756366.2025.2456282","DOIUrl":"10.1080/14756366.2025.2456282","url":null,"abstract":"Alzheimer's disease (AD) is a major neurodegenerative disorder more common in older adults. One of the leading AD hypotheses involves the amyloid beta (A) production, it is associated to oxidative stress, neuroinflammation, and neurovascular damage. The interaction of A with the blood vessel wall contributes to the disruption of the blood-brain barrier (BBB), allowing neutrophil infiltration containing the myeloperoxidase enzyme (MPO), which produces hypochlorous acid (HOCl) a potent oxidant. Also, MPO could be released from the microglia cells and interact with the amyloid beta plaques. This review aims to study the role of MPO in the progression of AD, in particular its contribution to oxidative stress and neuroinflammation. Furthermore, to explore the MPO-potential as AD-biomarker to evaluate the therapeutic potential of its inhibitors to mitigate the neurotoxicity. Finally, revise MPO inhibitors that could act as dual inhibitors acting on MPO and acetylcholinesterase and or another target involved in AD.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2456282"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414438","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

Chalcones inhibit firefly bioluminescence dependent on A and B-ring substitution pattern - a structure-activity study combined with molecular docking. 查尔酮抑制萤火虫生物发光依赖于A和b环取代模式-结合分子对接的结构-活性研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-06-09 DOI: 10.1080/14756366.2025.2509657

Corinna Urmann, Michael Kirchinger, Herbert Riepl

{"title":"Chalcones inhibit firefly bioluminescence dependent on A and B-ring substitution pattern - a structure-activity study combined with molecular docking.","authors":"Corinna Urmann, Michael Kirchinger, Herbert Riepl","doi":"10.1080/14756366.2025.2509657","DOIUrl":"10.1080/14756366.2025.2509657","url":null,"abstract":"Chalcones represent a privileged scaffold in medicinal chemistry, with pyranochalcones, featuring an additional chromane-like ring, identified as neurogenic and neuroprotective. Reporter gene assays, often used to study these and other effects, can produce false positives due to firefly luciferase stabilisation by inhibitors. The present study demonstrates that pyranochalcones inhibit firefly luciferase activity, with inhibition levels ranging from none to 100% and IC50 values of 7.82 µM to 92.99 µM. Furthermore, molecular docking offers potential structure-based explanations for the observed selectivity of compounds towards firefly luciferase inhibition. Even slight modifications in the molecular structure lead to significant changes in luciferase inhibition, underscoring the importance of these findings for understanding structure-activity relationships in reporter gene assays. Accordingly, caution is advised when using reporter gene assays based on firefly luciferase and pyranochalcones, as the IC50 values are within the range of concentrations commonly used in both in vivo and in vitro assays.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2509657"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248221","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

Investigation of the potential of phytochemicals derived from citrus peels to inhibit digestive enzymes: an overture to the management of lifestyle diseases. 从柑橘皮中提取的植物化学物质抑制消化酶的潜力的研究：对生活方式疾病管理的序曲。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-10-01 DOI: 10.1080/14756366.2025.2564800

Lebohang Moloi, Sana Samson, Kadima Tshiyoyo, Kamogelo Maluleke, Marni Oberholzer, Itumeleng Baloyi, Samkelo Malgas

{"title":"Investigation of the potential of phytochemicals derived from citrus peels to inhibit digestive enzymes: an overture to the management of lifestyle diseases.","authors":"Lebohang Moloi, Sana Samson, Kadima Tshiyoyo, Kamogelo Maluleke, Marni Oberholzer, Itumeleng Baloyi, Samkelo Malgas","doi":"10.1080/14756366.2025.2564800","DOIUrl":"10.1080/14756366.2025.2564800","url":null,"abstract":"The food industry relies on citrus fruits for juice, canned fruit, and jam, creating significant waste from peels, seeds, and pomace. This waste contains valuable phytochemicals like carotenoids, essential oils, (poly)phenols, pectin, and vitamins, which can be used as nutraceuticals or key ingredients in functional foods for managing diabetes and obesity. Repurposing citrus peel waste offers an excellent opportunity to advance biorefineries and the bioeconomy. Compounds derived from citrus have attracted attention for their potential therapeutic effects on diabetes and obesity, and their effectiveness depends on various mechanisms. This review summarises citrus-derived phytochemicals that inhibit α-glucosidase and pancreatic lipase in vitro, highlighting their potential as anti-diabetic and anti-obesity compounds. We also discuss progress in using molecular docking screening against key drug targets linked to type II diabetes and obesity. This review explores novel citrus phytochemicals for the development of nutraceuticals and functional food ingredients with enhanced health benefits.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2564800"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199612","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 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