ChemMedChem最新文献_第3页

Balinatunfib: A Clinical Oral Small Molecule TNFα Inhibitor Balinatunfib：临床口服小分子TNFα抑制剂。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-19 DOI: 10.1002/cmdc.202500258

Alexander Dömling, Tad A. Holak

{"title":"Balinatunfib: A Clinical Oral Small Molecule TNFα Inhibitor","authors":"Alexander Dömling, Tad A. Holak","doi":"10.1002/cmdc.202500258","DOIUrl":"10.1002/cmdc.202500258","url":null,"abstract":"Most diseases are accompanied by an inflammatory response, making effective pharmacological control highly desirable. Tumor necrosis factor alpha (TNFα) is a key cytokine driving inflammatory and autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Although biological TNFα inhibitors revolutionized treatment, they have drawbacks including lacking blood–brain barrier penetration, parenteral administration, and immunogenicity. Recent studies highlight the potential of small-molecule approaches to target TNFα by stabilizing an asymmetrical, receptor-incompetent trimer conformation. Balinatunfib (also known as SAR441566) is an orally available small molecule designed to exploit this mechanism, thereby preventing TNFα from effectively binding to its receptors. In preclinical models, balinatunfib reduces inflammation comparably to biologic therapies, yet avoids the complexities of large protein therapeutics. This allosteric strategy involves capturing a sampled but distorted state of TNFα, thereby blocking receptor clustering and downstream proinflammatory signaling. The oral route of administration confers practical advantages in terms of patient compliance and could facilitate drug access to sites traditionally less amenable to biologics, such as the central nervous system. By demonstrating that small molecules can achieve high-affinity, conformation-based inhibition of TNFα, balinatunfib, and related compounds may result in a new area of orally administered therapies that advance the management of TNFα-mediated diseases.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 14","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Proton first: rationalizing a proton transfer in a protein-fragment complex. 质子优先：使蛋白质片段复合物中的质子转移合理化。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-18 DOI: 10.1002/cmdc.202500244

Helge Vatheuer, Jonas Paulus, Lisa Johannknecht, Gerald Keller, Rebecca Maria Ziora, Lukas Stelzl, Paul Czodrowski

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Front Cover: (ChemMedChem 12/2025) 封面：（ChemMedChem 12/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-17 DOI: 10.1002/cmdc.202581201

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Efficacy of DNA Intercalator-Conjugated Triplex-Forming Oligonucleotide as Anticancer Agent. DNA插入物偶联三聚体寡核苷酸抗癌作用的研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-12 DOI: 10.1002/cmdc.202500325

Haruki Toyama, Akira Toriba, Atsushi Shibata, Takehiko Wada, Asako Yamayoshi, Yu Mikame

{"title":"Efficacy of DNA Intercalator-Conjugated Triplex-Forming Oligonucleotide as Anticancer Agent.","authors":"Haruki Toyama, Akira Toriba, Atsushi Shibata, Takehiko Wada, Asako Yamayoshi, Yu Mikame","doi":"10.1002/cmdc.202500325","DOIUrl":"https://doi.org/10.1002/cmdc.202500325","url":null,"abstract":"A triplex-forming oligonucleotide (TFO) can form a sequence-specific triple helix via Hoogsteen hydrogen bonding to polypurine tracts within a major groove side of a DNA duplex. Triplex formation can induce a double-strand break, and this phenomenon at the amplified gene loci can selectively induce the cell death of cancer cells with specific gene amplification. However, the relationship between the binding affinity of TFO for target gene loci and the cell death response remains unclear. In this study, we aimed to develop DNA intercalator-conjugated TFOs with higher affinity for the human epidermal growth factor receptor type2 (HER2) gene, which is often amplified in breast cancer cells, than the unmodified TFO. The binding affinity of the TFOs for the target DNA duplex was analyzed using nondenaturing polyacrylamide gel electrophoresis, and one of the DNA intercalator-conjugated TFOs showed a higher binding affinity for the target duplex than the unmodified TFO. We also evaluated the cell death responses induced by these TFOs using the WST-8 assay, suggesting that the higher binding affinity of the TFO for amplified gene loci can lead to a stronger cell death response of cancer cells with specific gene amplification.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500325"},"PeriodicalIF":3.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281816","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}

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Antiprotozoal Activity of Highly Substituted Pyrazole and Pyrimidine Derivatives. 高取代吡唑和嘧啶衍生物的抗原虫活性。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-12 DOI: 10.1002/cmdc.202500154

Matteo Lusardi, Nicoletta Basilico, Erika Iervasi, Chiara Brullo, Silvia Parapini, Marco Ponassi, Camillo Rosano, Andrea Spallarossa

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Design, Synthesis, and Biological Evaluation of Evodiamine Derivatives as Antibody-Drug Conjugate (ADC) Payloads. evoloo二胺衍生物作为抗体-药物偶联物（ADC）有效载荷的设计、合成和生物学评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-05 DOI: 10.1002/cmdc.202500268

Ruifeng Liu, Yanfang Duan, Jing Jiang, Weihua Bian, Meiying Zhu

{"title":"Design, Synthesis, and Biological Evaluation of Evodiamine Derivatives as Antibody-Drug Conjugate (ADC) Payloads.","authors":"Ruifeng Liu, Yanfang Duan, Jing Jiang, Weihua Bian, Meiying Zhu","doi":"10.1002/cmdc.202500268","DOIUrl":"https://doi.org/10.1002/cmdc.202500268","url":null,"abstract":"Natural product evodiamine derivatives exhibit multitarget bioactivities as dual TOPO I/II inhibitors, demonstrating remarkable potential in antitumor applications. Based on the evodiamine derivative D7-03, six derivatives were synthesized. In vitro screening showed that D7-09 had the strongest anti-tumor activity (IC50 = 9.75-26.11 nM) but poor hydrophobicity and solubility. D7-03, with nM-level cytotoxicity, better physicochemical properties, and high yield, was chosen as the core payload for ADC construction. The active molecule D7-03 was further explored as an antibody-drug conjugate (ADC) payload by constructing four linker-toxin complexes. These complexes were conjugated with trastuzumab to generate ADC candidate molecules. Notably, Ab-DL07-D7-03 exhibited superior activity (IC50 = 8.369 nM and 4.899 nM in HCC1954 and NCI-N87 cells, respectively) compared to the control group Ab-LC08-SN38. This study is the first application of evodiamine derivatives as TOPO I / II dual inhibitors in the ADC field, which not only provides a new strategy for the development of ADC payloads but also enriches the innovative application of natural product small molecules in tumor-targeted therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500268"},"PeriodicalIF":3.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232804","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

Platinum N-Heterocyclic Carbene Complexes Based on Adenosine: Synthesis and Antiproliferative Studies. 基于腺苷的铂n -杂环卡宾配合物：合成及抗增殖研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-04 DOI: 10.1002/cmdc.202500368

Giulia Orsini, Andreia Marinho, Claudia Nunes, Ana Petronilho

引用次数: 0

Tetrahydrofuran-containing Pharmaceuticals: Targets, Pharmacological Activities, and Their SAR Studies. 含四氢呋喃的药物：靶点、药理活性及其SAR研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-04 DOI: 10.1002/cmdc.202500259

Yiou Mei, Yunfei Du

引用次数: 0

Front Cover: Carborane-Based Analogs of Celecoxib and Flurbiprofen, their COX Inhibition Potential, and COX Selectivity Index (ChemMedChem 11/2025) 封面：塞来昔布和氟比洛芬的碳硼烷类类似物，它们的COX抑制潜能和COX选择性指数（ChemMedChem 11/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202581101

Lea Ueberham, Jonas Schädlich, Kim Schramke, Sebastian Braun, Christoph Selg, Markus Laube, Peter Lönnecke, Jens Pietzsch, Evamarie Hey-Hawkins

引用次数: 0

Novel 4,5-Dihydrothiazole-Phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents. 新型4,5-二氢噻唑-苯哌嗪衍生物：合成、对接研究及作为血清素能剂的药理评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-06-03 DOI: 10.1002/cmdc.202500288

Giorgia Andreozzi, Natalia Karkoszka, Rosa Sparaco, Angela Corvino, Beatrice Severino, Vincenzo Santagada, Elisa Magli, Ewa Gibuła-Tarłowska, Jolanta H Kotlińska, Kinga Gawel, Raffaele Capasso, Anna Lesniak, Nataliia Semenko, Agnieszka A Kaczor, Anna Bielenica, Grażyna Biała, Giuseppe Caliendo, Ewa Kędzierska, Ferdinando Fiorino

{"title":"Novel 4,5-Dihydrothiazole-Phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents.","authors":"Giorgia Andreozzi, Natalia Karkoszka, Rosa Sparaco, Angela Corvino, Beatrice Severino, Vincenzo Santagada, Elisa Magli, Ewa Gibuła-Tarłowska, Jolanta H Kotlińska, Kinga Gawel, Raffaele Capasso, Anna Lesniak, Nataliia Semenko, Agnieszka A Kaczor, Anna Bielenica, Grażyna Biała, Giuseppe Caliendo, Ewa Kędzierska, Ferdinando Fiorino","doi":"10.1002/cmdc.202500288","DOIUrl":"10.1002/cmdc.202500288","url":null,"abstract":"The synthesis of a new series of long-chain arylpiperazine as serotoninergic ligands (FG 1-18) is described. The combination of structural elements including heterocyclic nucleus, propyl chain, and 4,5-dihydrothiazol-2-ylphenylpiperazines leads to the preparation of different derivatives tested for their affinity toward 5-HT1A, 5-HT2A, and 5-HT2C receptors. The compounds with better affinity and selectivity binding profiles toward 5-HT1A and 5-HT2C (FG-1, FG-4, FG-5, FG-6, FG-7, FG-8, and FG-18) are selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies are performed. The results of pharmacological studies show that compounds FG-1, FG-5, FG-8, and FG-6 exert antidepressant-like effects, and FG-1, FG-18, FG-6, and FG-7 reveal also significant anxiolytic properties. Among the developed derivatives, the most promising compounds seem to be FG-1, which exhibit antidepressant, anxiolytic, and anticonvulsant properties, FG-7 and FG-18 that show features as anxiolytic combine to a pro-cognitive property and notable affinity and selectivity for 5-HT2C receptor, respectively.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500288"},"PeriodicalIF":3.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207262","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