Journal of Medicinal Chemistry最新文献_第10页

Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies. 发现新型 2-氨基吡啶基和 2-氨基嘧啶基衍生物作为治疗难治性实体瘤和血液恶性肿瘤的强效 CDK/HDAC 双抑制剂。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-08-23 DOI: 10.1021/acs.jmedchem.4c00837

Abdusaid Saidahmatov, Jianan Li, Shihao Xu, Xiaobei Hu, Xiangqian Gao, Weijuan Kan, Lixin Gao, Cong Li, Yuqiang Shi, Li Sheng, Peipei Wang, Yubo Zhou, Xuewu Liang, Jia Li, Hong Liu

{"title":"Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies.","authors":"Abdusaid Saidahmatov, Jianan Li, Shihao Xu, Xiaobei Hu, Xiangqian Gao, Weijuan Kan, Lixin Gao, Cong Li, Yuqiang Shi, Li Sheng, Peipei Wang, Yubo Zhou, Xuewu Liang, Jia Li, Hong Liu","doi":"10.1021/acs.jmedchem.4c00837","DOIUrl":"10.1021/acs.jmedchem.4c00837","url":null,"abstract":"Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Evaluation of Efficiency of Liposome-Entrapped Iridium(III) Complexes Inhibiting Tumor Growth In Vitro and In Vivo 评价脂质体包裹的铱(III)复合物在体外和体内抑制肿瘤生长的效率

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 DOI: 10.1021/acs.jmedchem.4c0102610.1021/acs.jmedchem.4c01026

Huiyan Hu, Jing Chen, Fan Zhang, Zhujun Sheng, Yan Yang*, Yufeng Xie, Lin Zhou and Yunjun Liu*,

{"title":"Evaluation of Efficiency of Liposome-Entrapped Iridium(III) Complexes Inhibiting Tumor Growth In Vitro and In Vivo","authors":"Huiyan Hu, Jing Chen, Fan Zhang, Zhujun Sheng, Yan Yang*, Yufeng Xie, Lin Zhou and Yunjun Liu*, ","doi":"10.1021/acs.jmedchem.4c0102610.1021/acs.jmedchem.4c01026","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01026https://doi.org/10.1021/acs.jmedchem.4c01026","url":null,"abstract":"In this paper, three new iridium(III) complexes: [Ir(piq)2(DFIPP)]PF6 (piq = deprotonated 1-phenylisoquinoline, DFIPP = 3,4-difluoro-2-(1H-imidazo[4,5-f][1,10]phenenthrolin-2-yl)phenol, 3a), [Ir(bzq)2(DFIPP)]PF6 (bzq = deprotonated benzo[h]quinoline, 3b), and [Ir(ppy)2(DFIPP)]PF6 (ppy = deprotonated 1-phenylpyridine, 3c), were synthesized and characterized. The complexes were found to be nontoxic to tumor cells via 3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide (MTT) assay. Surprisingly, its liposome-entrapped complexes 3alip, 3blip, and 3clip on B16 cells showed strong cytotoxicity (IC50 = 13.6 ± 2.8, 9.6 ± 1.1, and 18.9 ± 2.1 μM). Entry of 3alip, 3blip, and 3clip into B16 cells decreases mitochondrial membrane potential, regulates Bcl-2 family proteins, releases cytochrome c, triggers caspase family cascade reaction, and induces apoptosis. In addition, we also found that 3alip, 3blip, and 3clip triggered ferroptosis and autophagy. In vivo studies demonstrated that 3blip inhibited melanoma growth in C57 mice with a high inhibitory rate of 83.95%, and no organic damage was found in C57 mice.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Identification of CDK4/6 Inhibitors as Small Molecule NLRP3 Inflammasome Activators that Facilitate IL-1β Secretion and T Cell Adjuvanticity. 鉴定 CDK4/6 抑制剂作为促进 IL-1β 分泌和 T 细胞佐剂的小分子 NLRP3 炎症小体激活剂。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-08-20 DOI: 10.1021/acs.jmedchem.4c00516

Adam M Weiss, Marcos A Lopez, Matthew G Rosenberger, Jeremiah Y Kim, Jingjing Shen, Qing Chen, Trevor Ung, Udoka M Ibeh, Hannah Riley Knight, Nakisha S Rutledge, Bradley Studnitzer, Stuart J Rowan, Aaron P Esser-Kahn

{"title":"Identification of CDK4/6 Inhibitors as Small Molecule NLRP3 Inflammasome Activators that Facilitate IL-1β Secretion and T Cell Adjuvanticity.","authors":"Adam M Weiss, Marcos A Lopez, Matthew G Rosenberger, Jeremiah Y Kim, Jingjing Shen, Qing Chen, Trevor Ung, Udoka M Ibeh, Hannah Riley Knight, Nakisha S Rutledge, Bradley Studnitzer, Stuart J Rowan, Aaron P Esser-Kahn","doi":"10.1021/acs.jmedchem.4c00516","DOIUrl":"10.1021/acs.jmedchem.4c00516","url":null,"abstract":"Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1β release. Identifying small molecules that induce IL-1β release could allow targeted delivery and structure-function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1β release. We find that ribociclib induces IL-1β release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Deep Eutectic Solvents Enhancing Drug Solubility and Its Delivery. 深共晶溶剂提高药物的溶解度和输送能力

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-08-26 DOI: 10.1021/acs.jmedchem.4c01550

Anshu Sharma, Yea Rock Park, Aman Garg, Bong-Seop Lee

引用次数: 0

Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents. 选择性极光 A-TPX2 相互作用抑制剂作为靶向抗锑药物在体内具有疗效

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-08-27 DOI: 10.1021/acs.jmedchem.4c01165

Simon R Stockwell, Duncan E Scott, Gerhard Fischer, Estrella Guarino, Timothy P C Rooney, Tzu-Shean Feng, Tommaso Moschetti, Rajavel Srinivasan, Esther Alza, Alice Asteian, Claudio Dagostin, Anna Alcaide, Mathieu Rocaboy, Beata Blaszczyk, Alicia Higueruelo, Xuelu Wang, Maxim Rossmann, Trevor R Perrior, Tom L Blundell, David R Spring, Grahame McKenzie, Chris Abell, John Skidmore, Ashok R Venkitaraman, Marko Hyvönen

{"title":"Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.","authors":"Simon R Stockwell, Duncan E Scott, Gerhard Fischer, Estrella Guarino, Timothy P C Rooney, Tzu-Shean Feng, Tommaso Moschetti, Rajavel Srinivasan, Esther Alza, Alice Asteian, Claudio Dagostin, Anna Alcaide, Mathieu Rocaboy, Beata Blaszczyk, Alicia Higueruelo, Xuelu Wang, Maxim Rossmann, Trevor R Perrior, Tom L Blundell, David R Spring, Grahame McKenzie, Chris Abell, John Skidmore, Ashok R Venkitaraman, Marko Hyvönen","doi":"10.1021/acs.jmedchem.4c01165","DOIUrl":"10.1021/acs.jmedchem.4c01165","url":null,"abstract":"Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11403621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design Strategies. 针对溶剂前突变的激酶药物发现：从结构基础到设计策略。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-08-15 DOI: 10.1021/acs.jmedchem.4c00361

Yang Zhou, Jibo Kang, Xiaoyun Lu

引用次数: 0

Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat Acinetobacter baumannii: From Screening Impurity to In Vivo Efficacy. Cerastecin 抑制脂寡糖转运体 MsbA 以抗击鲍曼不动杆菌：从筛选杂质到体内疗效。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-08-22 DOI: 10.1021/acs.jmedchem.4c01277

Jason W Skudlarek, Andrew J Cooke, Helen J Mitchell, Kerim Babaoglu, Anthony W Shaw, Ling Tong, Ashley B Nomland, Marc Labroli, Deyou Sha, James J Mulhearn, Chengwei Wu, Sarah W Li, Douglas C Beshore, Jonathan M E Hughes, Matthieu Jouffroy, Hao Wang, Carl J Balibar, Ronald E Painter, Pamela Shen, Henry S Lange, Andrii Ishchenko, Yun-Ting Chen, Daniel J Klein, Rodger W Tracy, Randy R Miller, Tamara D Cabalu, Zhe Wu, Andrew Leithead, Giovanna Scapin, Alan W Hruza, Liudmila Dzhekieva, Marina Bukhtiyarova, Michelle F Homsher, Min Xu, Carolyn Bahnck-Teets, David McKenney, Alexei V Buevich, Jian Liu, Li-Kang Zhang, Tao Meng, Terri Kelly, Edward DiNunzio, Stephen Soisson, Robert K Y Cheng, Michael Hennig, Izzat Raheem, Scott S Walker

{"title":"Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat Acinetobacter baumannii: From Screening Impurity to In Vivo Efficacy.","authors":"Jason W Skudlarek, Andrew J Cooke, Helen J Mitchell, Kerim Babaoglu, Anthony W Shaw, Ling Tong, Ashley B Nomland, Marc Labroli, Deyou Sha, James J Mulhearn, Chengwei Wu, Sarah W Li, Douglas C Beshore, Jonathan M E Hughes, Matthieu Jouffroy, Hao Wang, Carl J Balibar, Ronald E Painter, Pamela Shen, Henry S Lange, Andrii Ishchenko, Yun-Ting Chen, Daniel J Klein, Rodger W Tracy, Randy R Miller, Tamara D Cabalu, Zhe Wu, Andrew Leithead, Giovanna Scapin, Alan W Hruza, Liudmila Dzhekieva, Marina Bukhtiyarova, Michelle F Homsher, Min Xu, Carolyn Bahnck-Teets, David McKenney, Alexei V Buevich, Jian Liu, Li-Kang Zhang, Tao Meng, Terri Kelly, Edward DiNunzio, Stephen Soisson, Robert K Y Cheng, Michael Hennig, Izzat Raheem, Scott S Walker","doi":"10.1021/acs.jmedchem.4c01277","DOIUrl":"10.1021/acs.jmedchem.4c01277","url":null,"abstract":"Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 of Covalent MLKL PROTAC Degraders via Optimization of a Theophylline Derivative Ligand for Treating Necroptosis. 通过优化用于治疗坏死性疾病的茶碱衍生物配体，发现共价 MLKL PROTAC 降解剂。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-08-24 DOI: 10.1021/acs.jmedchem.4c00949

Shang Li, Liangliang Ma, Xinxin Li, Yuhan Jiang, Zhongwen Luo, Fucheng Yin, Yonglei Zhang, Yifan Chen, Siyuan Wan, Han Zhou, Lingyi Kong, Xiaobing Wang

{"title":"Discovery of Covalent MLKL PROTAC Degraders via Optimization of a Theophylline Derivative Ligand for Treating Necroptosis.","authors":"Shang Li, Liangliang Ma, Xinxin Li, Yuhan Jiang, Zhongwen Luo, Fucheng Yin, Yonglei Zhang, Yifan Chen, Siyuan Wan, Han Zhou, Lingyi Kong, Xiaobing Wang","doi":"10.1021/acs.jmedchem.4c00949","DOIUrl":"10.1021/acs.jmedchem.4c00949","url":null,"abstract":"Mixed lineage kinase domain-like pseudokinase (MLKL) initiates necroptosis and could serve as a therapeutic target related to a series of human diseases. Proteolysis-targeting chimeras (PROTACs) are useful tools for degrading pathological proteins and blocking disease processes. Using computer-aided modeling and molecular dynamics simulations, we developed a series of covalent MLKL PROTACs by linking and optimizing a theophylline derivative that covalently targets MLKL. Via structure-activity relationship studies, MP-11 was identified as a potent MLKL PROTAC degrader. Furthermore, MP-11 showed lower toxicity than the original MLKL ligand, exhibiting nanomolar-scale antinecroptotic activity on human cell lines. Xenograft model studies showed that MP-11 effectively degraded MLKL in vivo. Importantly, our study demonstrates that the covalent binding strategy is an effective approach for designing MLKL-targeting PROTACs, serving as a model for developing PROTACs to treat future necroptosis-related human diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Structure-Based Design and Development of Phosphine Oxides as a Novel Chemotype for Antibiotics that Dysregulate Bacterial ClpP Proteases. 以结构为基础设计和开发氧化膦，将其作为可抑制细菌 ClpP 蛋白酶的抗生素的新型化学类型。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-09-02 DOI: 10.1021/acs.jmedchem.4c00773

Funing Lin, Mark F Mabanglo, Jin Lin Zhou, Gursonika Binepal, Marim M Barghash, Keith S Wong, Scott D Gray-Owen, Robert A Batey, Walid A Houry

{"title":"Structure-Based Design and Development of Phosphine Oxides as a Novel Chemotype for Antibiotics that Dysregulate Bacterial ClpP Proteases.","authors":"Funing Lin, Mark F Mabanglo, Jin Lin Zhou, Gursonika Binepal, Marim M Barghash, Keith S Wong, Scott D Gray-Owen, Robert A Batey, Walid A Houry","doi":"10.1021/acs.jmedchem.4c00773","DOIUrl":"10.1021/acs.jmedchem.4c00773","url":null,"abstract":"A series of arylsulfones and heteroarylsulfones have previously been demonstrated to dysregulate the conserved bacterial ClpP protease, causing the unspecific degradation of essential cellular housekeeping proteins and ultimately resulting in cell death. A cocrystal structure of a 2-β-sulfonylamide analog, ACP1-06, with Escherichia coli ClpP showed that its 2-pyridyl sulfonyl substituent adopts two orientations in the binding site related through a sulfone bond rotation. From this, a new bis-aryl phosphine oxide scaffold, designated as ACP6, was designed based on a \"conformation merging\" approach of the dual orientation of the ACP1-06 sulfone. One analog, ACP6-12, exhibited over a 10-fold increase in activity over the parent ACP1-06 compound, and a cocrystal X-ray structure with ClpP confirmed its predicted binding conformation. This allowed for a comparative analysis of how different ligand classes bind to the hydrophobic binding site. The study highlights the successful application of structure-based rational design of novel phosphine oxide-based antibiotics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Structural Optimization and Structure-Activity Relationship of 1H-Pyrazole-4-carboxylic Acid Derivatives as DNA 6mA Demethylase ALKBH1 Inhibitors and Their Antigastric Cancer Activity. 作为 DNA 6mA 去甲基化酶 ALKBH1 抑制剂的 1H-吡唑-4-羧酸衍生物的结构优化和结构活性关系及其抗胃癌活性

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-09-12 Epub Date: 2024-09-03 DOI: 10.1021/acs.jmedchem.4c01072

Feng Li, Liang Xiong, Jian Zhang, Yinping Guo, Ke Xu, Zijie Xiong, Yuyang Wang, Shanmian Ji, Aiping Tong, Linli Li, Shengyong Yang

{"title":"Structural Optimization and Structure-Activity Relationship of 1H-Pyrazole-4-carboxylic Acid Derivatives as DNA 6mA Demethylase ALKBH1 Inhibitors and Their Antigastric Cancer Activity.","authors":"Feng Li, Liang Xiong, Jian Zhang, Yinping Guo, Ke Xu, Zijie Xiong, Yuyang Wang, Shanmian Ji, Aiping Tong, Linli Li, Shengyong Yang","doi":"10.1021/acs.jmedchem.4c01072","DOIUrl":"10.1021/acs.jmedchem.4c01072","url":null,"abstract":"DNA N6-methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1H-pyrazole-4-carboxylic acid derivative 29. The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29, we prepared a prodrug of 29 (29E), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E. Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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