ChemMedChem最新文献_第6页

Repurposing of Inhibitors of Plasmodial Aspartate Transcarbamoylase Toward Trypanosoma Cruzi 对克氏锥虫的天门冬氨酸转氨基甲酰基酶抑制剂的再利用。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-26 DOI: 10.1002/cmdc.202500817

Siyao Chen, Monica Cal, Queenie Mondile, Rick Oerlemans, Mukim Mayur Shashikant, Alexander S. S. Dömling, Özlem Tastan Bishop, Pascal Mäser, Matthew R. Groves

{"title":"Repurposing of Inhibitors of Plasmodial Aspartate Transcarbamoylase Toward Trypanosoma Cruzi","authors":"Siyao Chen, Monica Cal, Queenie Mondile, Rick Oerlemans, Mukim Mayur Shashikant, Alexander S. S. Dömling, Özlem Tastan Bishop, Pascal Mäser, Matthew R. Groves","doi":"10.1002/cmdc.202500817","DOIUrl":"10.1002/cmdc.202500817","url":null,"abstract":"Aspartate transcarbamoylase (ATC) catalyzes the committed and rate-limiting step in the pyrimidine de novo biosynthesis pathway. While previously suggested to be a potential target for antimalarial, antitubercular, and antioncologic drug discovery, we hypothesized that an existing compound library of ATC inhibitors designed from one scaffold by fragment screening against Plamodium falciparum ATC (PfATC) may also contain inhibitors of Trypanosoma cruzi ATC (TcATC). In this manuscript, we screened the 70-member library at 35 μM against 50 nM TcATC, and in these initial experiments, 34 compounds showed over 90% inhibition. Of the 34 compounds, 5 compounds demonstrated IC50 values of lower than 250 nM in a follow-up enzymatic half inhibition concentration analysis. Kinetic studies on one of these compounds indicate that they inhibit TcATC in a noncompetitive manner, and a druggable allosteric pocket is seen in the available crystal structure. While cocrystallization and soaking experiments were unsuccessful, molecular modeling was performed to assess potential binding modes. Two of the best-performing compounds were selected for a cellular assay, showing EC50s of 7.4 µM and 6.5 µM. However, significant cotoxicity was also observed, demonstrating that further elaboration of the compounds is necessary. These results suggest that this compound library might be a starting point for antitrypanosomatid drug discovery.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519449","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}

引用次数: 0

Novel Vancomycin-β-Lactam Hybrids: Structure–Activity Relationships and Therapeutic Potential Against VISA and VRE 新型万古霉素-β-内酰胺杂交种：构效关系及抗VISA和VRE的治疗潜力。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-26 DOI: 10.1002/cmdc.202501084

Taopeng Chang, Fang Li, Chengtao Feng, Xiaowen Wang, Dongliang Guan

{"title":"Novel Vancomycin-β-Lactam Hybrids: Structure–Activity Relationships and Therapeutic Potential Against VISA and VRE","authors":"Taopeng Chang, Fang Li, Chengtao Feng, Xiaowen Wang, Dongliang Guan","doi":"10.1002/cmdc.202501084","DOIUrl":"10.1002/cmdc.202501084","url":null,"abstract":"Antimicrobial resistance (AMR) poses a significant global public health challenge. Vancomycin and β-lactam antibiotics, critical for treating multidrug-resistant (MDR) bacterial infections, are hindered by resistant strains such as vancomycin-resistant Enterococci (VRE) and vancomycin-intermediate Staphylococcus aureus, as well as β-lactamase-mediated resistance. This article leverages the complementary mechanisms of these antibiotics, which target bacterial cell wall synthesis, to develop vancomycin-β-lactam hybrids as a novel strategy against AMR. Through chemical modification, β-lactam fragments were introduced at the carboxyl (C), resorcinol (R), and amine (N) termini of vancomycin, yielding multiple hybrid series. In vitro activity assays revealed that C-terminal modified vancomycin–penicillin hybrids exhibited superior efficacy, with compound 6a–6g reducing the minimum inhibitory concentration against strains such as VREs by 512–1024-fold compared to vancomycin, achieving activity comparable to oritavancin in certain strains. In vitro safety evaluations demonstrated low cytotoxicity of 6a against human kidney (HK2) and embryonic kidney (HEK293) cell lines. These findings establish 6a as a promising drug candidate, offering a novel therapeutic option for MDR infections.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519432","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

Synthesis of β-Carboline-Based Dimers and Hybrids and Anti-Methicillin-Resistant Staphylococcus aureus Properties by Targeting FtsZ β-羰基二聚体和杂交种的合成及靶向FtsZ抗耐甲氧西林金黄色葡萄球菌的特性

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-26 DOI: 10.1002/cmdc.202501101

Yingxue Fu, Xuanyu Cao, Weida Liang, Hongda Qiu, Xing Zhao, Bowen Han, Zhaoxiang Peng, Lingling Zhao, Xuan Zhang, Xiao Wang, Hongze Liang

{"title":"Synthesis of β-Carboline-Based Dimers and Hybrids and Anti-Methicillin-Resistant Staphylococcus aureus Properties by Targeting FtsZ","authors":"Yingxue Fu, Xuanyu Cao, Weida Liang, Hongda Qiu, Xing Zhao, Bowen Han, Zhaoxiang Peng, Lingling Zhao, Xuan Zhang, Xiao Wang, Hongze Liang","doi":"10.1002/cmdc.202501101","DOIUrl":"10.1002/cmdc.202501101","url":null,"abstract":"The upsurging antibiotic resistance crisis underscores the urgent need for discovering agents with new molecular scaffolds. Dimerization and hybridization represent the most commonly employed approaches and are promising strategies for developing new antibacterial entities to combat antibiotic resistance. In this study, two series of dimeric β-carbolines and tacrine-β-carboline hybrids were synthesized. The tacrine-β-carboline derivatives demonstrated potent activity against Gram-positive bacteria (MIC = 0.195–50 μg/mL), exhibiting particularly strong inhibition against methicillin-resistant Staphylococcus aureus (MRSA). Mechanistic evidence demonstrates that tacrine-β-carboline hybrids exert antibacterial effects by disrupting both bacterial cell wall and membrane integrity and the function of filamentous temperature-sensitive mutant Z (FtsZ), a pivotal cell division protein. Specifically, these compounds drive FtsZ polymerization by promoting monomer assembly and stabilizing the resultant polymeric structures, concomitantly suppressing GTPase activity. Molecular docking and dynamics simulations further elucidated binding interactions within the FtsZ nucleotide-binding domain (NBD). This work might provide an insight into developing novel therapeutics targeting drug-resistant bacterial pathogens.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519435","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

An Internal Sulfur–Lone Pair Interaction Enabled the Discovery of Potent and Sub-Family Selective PKMYT1 Inhibitors 内部硫-孤对相互作用使得发现了有效的亚家族选择性PKMYT1抑制剂。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-26 DOI: 10.1002/cmdc.202501029

Yazhou Wang, Chao Wang, Xiaomin Wang, Tingting Liu, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Xiao Ding, Alex Zhavoronkov

引用次数: 0

Comprehensive Magnetic Resonance Imaging Relaxometry of Gadolinium-Based Contrast Agents: A Systematic Study of Transmetallation and Transchelation Processes With Zinc Ions and Heparin 钆基造影剂的综合磁共振成像弛豫测量：锌离子和肝素的金属转化和转运过程的系统研究。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-26 DOI: 10.1002/cmdc.202501096

Patrick Werner, Leif Schröder

{"title":"Comprehensive Magnetic Resonance Imaging Relaxometry of Gadolinium-Based Contrast Agents: A Systematic Study of Transmetallation and Transchelation Processes With Zinc Ions and Heparin","authors":"Patrick Werner, Leif Schröder","doi":"10.1002/cmdc.202501096","DOIUrl":"10.1002/cmdc.202501096","url":null,"abstract":"Gadolinium-based contrast agents (GBCAs) are essential in medical imaging, but concerns remain about their long-term safety. An increasing number of studies indicate that gadolinium can accumulate in human tissues. The initial step is transmetallation, whereby endogenous ions displace Gd(III) ions from its chelate. Subsequently, a transchelation process allows ion binding to macromolecules, such as glycosaminoglycans (GAGs), and tissue deposits may form. However, the clinical impact and potential connection to gadolinium deposition disease remain uncertain and require further research. In this study, magnetic resonance imaging relaxometry was employed to investigate the molecular interactions of eight clinically relevant GBCAs with Zn(II) ions and GAGs. Taking advantage of the characteristic relaxivity changes of Gd(III) ions in different environments enabled detection and quantification of free Gd(III) ions, as well as of the macromolecule-bound species. The investigation revealed distinct relaxivity patterns of Gd-accessible water that are specific for each GBCA, highlighting differences in intrinsic stability when challenged by competing ions or alternative chelators. Evaluation of transitions between equilibrium states enables comparative assessment of reaction kinetics for deeper insights into the observables of GBCA behavior. Thus, relaxometry emerges as a robust analytical platform, offering valuable guidance for improving existing contrast agents and designing safer, more stable alternatives.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508016","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}

引用次数: 0

Strategic Key Performance Indicators for AI in Lead Optimization 人工智能在潜在客户优化中的战略关键绩效指标。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-22 DOI: 10.1002/cmdc.202501089

Theodor Theis, Stefanie Flohr, Hayley Binch, Werngard Czechtizky, Ewa Chudyk, Markus Klein, Mireille Krier, Franz von Nussbaum

{"title":"Strategic Key Performance Indicators for AI in Lead Optimization","authors":"Theodor Theis, Stefanie Flohr, Hayley Binch, Werngard Czechtizky, Ewa Chudyk, Markus Klein, Mireille Krier, Franz von Nussbaum","doi":"10.1002/cmdc.202501089","DOIUrl":"10.1002/cmdc.202501089","url":null,"abstract":"With increasing cost and failure rates in the pharmaceutical R&D process not fundamentally improving over the last decade, pressure remains high to increase the probability of success to improve the effectiveness of pharmaceutical R&D. The broad introduction of AI into the R&D landscape over the last years holds the promise to lift pharmaceutical R&D out of its productivity problem, as preliminary analyses suggest that “AI-native” companies may be outpacing traditional peers. However, harnessing this potential requires moving beyond measuring technical model performance (e.g., predictive accuracy) to measuring strategic impact. In this perspective, members of the EFMC2 community—focused on advancing the collaboration between computational and medicinal chemists—discuss the challenges of applying key performance indicators (KPIs) in the idiosyncratic environment of drug discovery. We argue that the shift from expert-driven computer-aided drug design (CADD) to semiautonomous AI necessitates a new framework of impact-oriented KPIs. We provide recommendations for designing these strategic indicators to drive adoption, foster innovation, and objectively assess whether digital tools are delivering top-line impact.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496976","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}

引用次数: 0

Insights Into Vepdegestrant (ARV-471): The First-in-Class Estrogen Receptor Proteolysis-Targeting Chimera Approaching Food and Drug Administration Approval for Breast Cancer Vepdegestrant (ARV-471)：首个雌激素受体蛋白水解靶向嵌合体即将获得美国食品和药物管理局批准用于乳腺癌。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-22 DOI: 10.1002/cmdc.202501111

Chao Tang, Bin Tian, Bingxing Zhang, Yunfei Zhang, Changhua Ke, Mengxin Chen, Meiyan Wei, Wen Wang, Xintao Deng, Qiannan Zhang, Mengzhou Wang, Juan Xia, Meiling He, Chengyuan Liang, Lei Tian

{"title":"Insights Into Vepdegestrant (ARV-471): The First-in-Class Estrogen Receptor Proteolysis-Targeting Chimera Approaching Food and Drug Administration Approval for Breast Cancer","authors":"Chao Tang, Bin Tian, Bingxing Zhang, Yunfei Zhang, Changhua Ke, Mengxin Chen, Meiyan Wei, Wen Wang, Xintao Deng, Qiannan Zhang, Mengzhou Wang, Juan Xia, Meiling He, Chengyuan Liang, Lei Tian","doi":"10.1002/cmdc.202501111","DOIUrl":"10.1002/cmdc.202501111","url":null,"abstract":"Vepdegestrant (ARV-471) is an orally bioavailable, proteolysis-targeting chimera (PROTAC)-based estrogen receptor (ER) degrader and is among the most clinically advanced ER-targeting PROTAC degraders, identified through a rational medicinal chemistry optimization campaign. It is being developed as an oral small-molecule endocrine therapy for advanced or metastatic ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, with particular relevance for tumors harboring ESR1 mutations. On June 6, 2025, Arvinas and Pfizer submitted a New Drug Application (NDA) for vepdegestrant to the U.S. Food and Drug Administration (FDA), representing an important step in the clinical translation of PROTAC technology. This review summarizes the design, synthesis, degradation mechanism, preclinical pharmacology, and clinical development of vepdegestrant and discusses the broader implications and future prospects of oral PROTAC-based ER degraders in breast cancer therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496967","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

Cyclic Peptides Radiopharmaceuticals: A Concise Review of Ligand Identification, Radiolabeling, and Clinical Progress 环肽放射性药物：配体鉴定、放射性标记和临床进展的简明综述。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-22 DOI: 10.1002/cmdc.202501005

Xiushuang Yuan, Haoyuan Jia, Liru Chen, Jiang Li, Wei Cheng, Kuan Hu

{"title":"Cyclic Peptides Radiopharmaceuticals: A Concise Review of Ligand Identification, Radiolabeling, and Clinical Progress","authors":"Xiushuang Yuan, Haoyuan Jia, Liru Chen, Jiang Li, Wei Cheng, Kuan Hu","doi":"10.1002/cmdc.202501005","DOIUrl":"10.1002/cmdc.202501005","url":null,"abstract":"Radiopharmaceuticals are the foundation of nuclear medicine, with targeted ligands forming their core components. Peptide radiopharmaceuticals have demonstrated significant advantages in clinical practice and occupy a pivotal position among targeted radiopharmaceuticals approved by the FDA. Cyclic peptides represent an increasingly important class of radiopharmaceutical ligands, with remarkable progress achieved in recent years. Compared to linear peptides, they demonstrate greater targeting specificity and affinity, offering considerable potential for clinical translation. This article provides an overview of the general workflow and key considerations in the research and development of cyclic peptide radiopharmaceuticals, which includes the acquisition of cyclic peptide ligands, radionuclide labeling, and in vitro and in vivo studies. It outlines the major pre-clinical and clinical research advances in cyclic peptide radiopharmaceuticals and offers a prospective outlook on their future development. These developments highlight the promise of cyclic peptides to overcome key challenges in radiopharmaceutical development, such as improving tumor uptake/retention and pharmacodynamics. The aim is to provide a reference for professionals engaged in the development of novel radiopharmaceuticals, thereby accelerating innovation in radiopharmaceutical research and development.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497011","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

Self-Immolative Systems in Diagnostic and Therapeutic Applications 自焚系统在诊断和治疗中的应用。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-16 DOI: 10.1002/cmdc.202500858

Windbedema Prisca Ouédraogo, Thomas Cailly, Valérie Collot

引用次数: 0

Nuclear-Targeted Boron-Lapatinib Hybrid for Enhanced Boron Neutron Capture Therapy in Advanced Thyroid Carcinoma 核靶向硼-拉帕替尼复合物增强硼中子俘获治疗晚期甲状腺癌。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-16 DOI: 10.1002/cmdc.202501074

Marcos Couto, Martina Buschittari, Marina Carpano, Susana Nievas, Belén Dávila, Antonella Pastini, Ignacio González, Marina Perona, María Sol Espain, Agustina Mariana Portu, Hugo Cerecetto, María Alejandra Dagrosa

{"title":"Nuclear-Targeted Boron-Lapatinib Hybrid for Enhanced Boron Neutron Capture Therapy in Advanced Thyroid Carcinoma","authors":"Marcos Couto, Martina Buschittari, Marina Carpano, Susana Nievas, Belén Dávila, Antonella Pastini, Ignacio González, Marina Perona, María Sol Espain, Agustina Mariana Portu, Hugo Cerecetto, María Alejandra Dagrosa","doi":"10.1002/cmdc.202501074","DOIUrl":"10.1002/cmdc.202501074","url":null,"abstract":"To enhance the effectiveness of boron neutron capture therapy (BNCT) for advanced thyroid carcinoma (ATC), we evaluated two previously synthesized boron-enriched derivatives of Lapatinib incorporating high-boron clusters. Lapatinib, a tyrosine kinase inhibitor (TKI), is clinically used in targeted therapy against tumor proliferation and progression. The compounds consisted of Lapatinib-pharmacophore linked either to an ortho-carborane cluster (Cmpd-1) or to a metallacarborane cobalta-bis-dicarbollide (COSAN) anion (Cmpd-2). In vitro studies using the ATC 8505C anaplastic thyroid carcinoma cells showed significant cellular uptake of both compounds. Neutron autoradiography revealed that Cmpd-2 is located predominantly within the nucleus, suggesting that nuclear targeting may contribute to its enhanced therapeutic potential. Subsequent BNCT irradiation experiments at the Argentine nuclear reactor RA-3 demonstrated a marked reduction in cell survival, decreased Ki-67 expression, and increased apoptosis for BNCT-Cmpd-2 compared with BNCT using boronophenylalanine (BPA, a standard positive control), neutron-alone, and control groups. In vivo studies in ATC xenografted nude mice confirmed the absence of systemic toxicity and a significant inhibition of tumor growth following Cmpd-2 treatment (p < 0.01). Boron biodistribution analyses revealed favorable tumor-to-blood ratios (>3) when Cmpd-2 was combined with BPA. Overall, these results support Cmpd-2 as a promising bimodal agent for targeted and neutron-based therapy of advanced thyroid cancer.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466452","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