ChemMedChem最新文献_第8页

Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein 发现 KW0113 是首个有效的 DNMT1 蛋白 PROTAC 降解剂

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-20 DOI: 10.1002/cmdc.202400467

Huihui Wang, Zhaoliang Wang, Linghao Hu, Bingjie Yang, Liangyi Zong, Dounan Xu, Bo Yu, Xiangqian Kong, Mingliang Wang

引用次数: 0

Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat 已获批准的 HIF 脯氨酰羟化酶抑制剂 Desidustat 和 Enarodustat 的晶体学和选择性研究

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-18 DOI: 10.1002/cmdc.202400504

Thomas P. Corner, Eidarus Salah, Anthony Tumber, Samanpreet Kaur, Yu Nakashima, Mark D. Allen, Lara I. Schnaubelt, Giorgia Fiorini, Lennart Brewitz, Christopher Schofield

{"title":"Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat","authors":"Thomas P. Corner, Eidarus Salah, Anthony Tumber, Samanpreet Kaur, Yu Nakashima, Mark D. Allen, Lara I. Schnaubelt, Giorgia Fiorini, Lennart Brewitz, Christopher Schofield","doi":"10.1002/cmdc.202400504","DOIUrl":"https://doi.org/10.1002/cmdc.202400504","url":null,"abstract":"Prolyl hydroxylase domain‐containing proteins 1‐3 (PHD1‐3) are 2‐oxoglutarate (2OG)‐dependent oxygenases catalysing C‐4 hydroxylation of prolyl residues in α‐subunits of the heterodimeric transcription factor hypoxia‐inducible factor (HIF), modifications that promote HIF‐α degradation via the ubiquitin‐proteasome pathway. Pharmacological inhibition of the PHDs induces HIF‐α stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia‐inducible factor‐α (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1‐3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA‐damage repair, and agrochemical resistance.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"8 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Bacterial Secondary Metabolites Embedded in Producer Cell Membranes and Antibiotics Targeting Their Biosynthesis 嵌入生产者细胞膜的细菌次生代谢物和针对其生物合成的抗生素

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-17 DOI: 10.1002/cmdc.202400469

Zhao Xia, Hao Xiang, Yi-Ming Shi

引用次数: 0

Ultrasound-Assisted Synthesis of Pyrazoline Derivatives as Potential Antagonists of RAGE-Mediated Pathologies: Insights from SAR Studies and Biological Evaluations 超声辅助合成吡唑啉衍生物作为 RAGE 介导的病理学的潜在拮抗剂：SAR 研究和生物评估的启示

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-17 DOI: 10.1002/cmdc.202400527

Anca-Elena Dascălu, Christophe Furman, Steve Lancel, Emmanuelle Lipka, Maxime Liberelle, Eric Boulanger, Alina Ghinet

{"title":"Ultrasound-Assisted Synthesis of Pyrazoline Derivatives as Potential Antagonists of RAGE-Mediated Pathologies: Insights from SAR Studies and Biological Evaluations","authors":"Anca-Elena Dascălu, Christophe Furman, Steve Lancel, Emmanuelle Lipka, Maxime Liberelle, Eric Boulanger, Alina Ghinet","doi":"10.1002/cmdc.202400527","DOIUrl":"https://doi.org/10.1002/cmdc.202400527","url":null,"abstract":"In the context of age-related disorders, the receptor of advanced glycation end products (RAGE), plays a pivotal role in the pathogenesis of these conditions by triggering downstream signaling pathways associated with chronic inflammation and oxidative stress. Targeting this inflammaging phenomenon with RAGE antagonists holds promise for interventions with broad implications in healthy aging and the management of age-related conditions. This study explores the structure-activity relationship (SAR) of pyrazoline-based RAGE antagonists synthesized using an ultrasound-assisted green one-pot two-steps methodology. Our investigation identifies phenylurenyl-pyrazoline 2g as a promising candidate, demonstrating superior efficiency compared to the reference antagonist Azeliragon (IC50 = 13 µM). Compound 2g exhibits potent inhibition of the AGE2-BSA/sRAGE interaction (IC50 = 22 µM) and favorable affinity in Microscale Thermophoresis (MST) assays (Kd = 17.1 µM), along with a favorable safety profile, with no apparent cytotoxicity observed in vitro in the MTS assay. These findings underscore the potential of pyrazoline-derived RAGE antagonists as therapeutic agents for addressing age-related disorders.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"8 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Medicinal Chemistry in Bosnia and Herzegovina ‐ Past, Present and Perspectives** 波斯尼亚和黑塞哥维那的药物化学--过去、现在和前景**

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-17 DOI: 10.1002/cmdc.202400669

Martin Kondža

{"title":"Medicinal Chemistry in Bosnia and Herzegovina ‐ Past, Present and Perspectives**","authors":"Martin Kondža","doi":"10.1002/cmdc.202400669","DOIUrl":"https://doi.org/10.1002/cmdc.202400669","url":null,"abstract":"Although Bosnia and Herzegovina has had a rich history in medicines and traditional medicines, it historically had poor activity regarding the field of medicinal chemistry in the country. However, this has changed recently as Bosnia and Herzegovina has shown immense potential in this field. A significant milestone occurred in 2019, with the establishment of the Organization Pharmaceutical Research Institute. This non‐governmental organization aims to improve medicinal chemistry in Bosnia and Herzegovina. Through research, partnerships, and educational initiatives, the organization has made substantial strides in promoting pharmaceutical research, education, and innovation. Moreover, the country‘s membership in the European Federation for Medicinal Chemistry and Chemical Biology (EFMC) has further facilitated collaboration with European experts, access to cutting‐edge knowledge and technologies, and harmonization with European standards. Looking to the future, this organization endeavors to improve healthcare, encourage innovation in medicinal chemistry, and promote the development of new therapies. With the efforts to establish an Association of Chemists in Bosnia and Herzegovina, the nation‘s scientific community is poised to flourish, contributing to the advancement of medicinal chemistry and healthcare in the region.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Front Cover: Rational Design of Novel Allosteric EYA2 Inhibitors as Potential Therapeutics for Multiple Brain Cancers (ChemMedChem 18/2024) 封面：作为多种脑癌潜在治疗药物的新型异位EYA2抑制剂的合理设计（ChemMedChem 18/2024）

IF 3.6 4区医学

ChemMedChem Pub Date : 2024-09-16 DOI: 10.1002/cmdc.202481801

Lukas Gardner, John Rossi, Brock Armstrong, Mia Muse, Alex LaVeck, Melanie A. Blevins, Lingdi Zhang, Dr. Heide L. Ford, Dr. Rui Zhao, Dr. Xiang Wang

引用次数: 0

Discovery of ICOS‐targeted small molecules using affinity selection mass spectrometry screening 利用亲和选择质谱筛选发现 ICOS 靶向小分子化合物

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-13 DOI: 10.1002/cmdc.202400545

Longfei Zhang, Laura Calvo-Barreiro, Victor de Sousa Batista, Katarzyna Świderek, Moustafa Gabr

{"title":"Discovery of ICOS‐targeted small molecules using affinity selection mass spectrometry screening","authors":"Longfei Zhang, Laura Calvo-Barreiro, Victor de Sousa Batista, Katarzyna Świderek, Moustafa Gabr","doi":"10.1002/cmdc.202400545","DOIUrl":"https://doi.org/10.1002/cmdc.202400545","url":null,"abstract":"Inducible T cell co‐stimulator (ICOS) is a positive immune checkpoint receptor expressed on the surface of activated T cells, which could promote cell function after being stimulated with ICOS ligand (ICOS‐L). Although clinical benefits have been reported in the ICOS modulation‐based treatment for cancer and autoimmune disease, current modulators are restricted in biologics, whereas ICOS‐targeted small molecules are lacking. To fill this gap, we performed an affinity selection mass spectrometry (ASMS) screening for ICOS binding using a library of 15,600 molecules. To the best of our knowledge, this is the first study that utilizes ASMS screening to discover small molecules targeting immune checkpoints. Compound 9 with a promising ICOS/ICOS‐L inhibitory profile (IC50 = 29.38 ± 3.41 µM) was selected as the template for the modification. Following preliminary structure‐activity relationship (SAR) study and molecular dynamic (MD) simulation revealed the critical role of the ortho‐hydroxy group on compound 9 in the ICOS binding, as it could stabilize the interaction via the hydrogen bond formation with residuals on the glycan, and the depletion could lead to an activity lost. This work validates a promising inhibitor for the ICOS/ICOS‐L interaction, and we anticipate future modifications could provide more potent modulators for this interaction.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"17 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Breaking Barriers in Photothermal Tumor Therapy: A Cascade of Strain‐Engineered Nanozyme in Action 打破肿瘤光热疗法的障碍：一连串应变工程纳米酶在发挥作用

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-13 DOI: 10.1002/cmdc.202400443

Srinidhi V. G., Huidrom Mangalsana, Amit Vernekar

引用次数: 0

Biomimetic Cell Membrane‐Coated Nanoparticles for Cancer Theranostics 用于癌症血清学的仿生细胞膜包覆纳米粒子

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-12 DOI: 10.1002/cmdc.202400410

Tiantian Jiang, Yiduo Zhan, Jiayao Ding, Zheming Song, Yijing Zhang, Jingchao Li, Ting Su

{"title":"Biomimetic Cell Membrane‐Coated Nanoparticles for Cancer Theranostics","authors":"Tiantian Jiang, Yiduo Zhan, Jiayao Ding, Zheming Song, Yijing Zhang, Jingchao Li, Ting Su","doi":"10.1002/cmdc.202400410","DOIUrl":"https://doi.org/10.1002/cmdc.202400410","url":null,"abstract":"Nanoparticles can enhance drugs accumulating at the tumor site and hold tremendous promise for achieving effective tumor treatment. However, due to the complexity of cancer heterogeneity and suppressive tumor microenvironment, the delivery of traditional nanoparticles has poor infiltration and off‐target effects, making it difficult to control the drug release rate and causing off‐target toxicity. In recent years, cell membrane‐coated biomimetic nanoparticles have been developed, which have both the natural characteristics of biomembranes and the physical characteristics of traditional nanoparticles, thus improving the homologous targeting ability of nanoparticles to tumor cells and better biocompatibility. In this paper, we reviewed the application of single cell membrane and hybrid cell membrane‐coated biomimetic nanoparticles in the integration for tumor diagnosis and treatment. We talked about the preparation methods of cell membrane‐coated nanoparticles, the targeting mechanisms, and the effects of imaging and therapeutic outcomes of different cell membrane‐coated biomimetic nanoparticles in detail. Finally, we discussed the existing problems and prospects of cell membrane‐coated biomimetic nanomaterials.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"27 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Flavonol‐ruthenium complexes as antioxidant and anticancer agents 作为抗氧化剂和抗癌剂的黄酮醇钌复合物

IF 3.4 4区医学

ChemMedChem Pub Date : 2024-09-12 DOI: 10.1002/cmdc.202400313

Tzenge-Lien Shih, Ting-Wei Wu, Yi-Cheng Chu, Chuan-Hsin Chang, Yu-Hui Hsieh, Mei-Hsin Tang, Pei-Hsuan Hsu, Jih-Jung Chen

引用次数: 0