Journal of Medicinal Chemistry最新文献_第2页

Discovery of P11–2: A Potent First-in-Class MNK1-Targeting PROTAC Degrader for the Treatment of Cancer P11-2的发现：一种有效的靶向mnk1治疗癌症的PROTAC降解剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-07 DOI: 10.1021/acs.jmedchem.5c00062

Zhongcheng Yang, Yuxia Liu, Zibin Liao, Lianru Chen, Zhiling Liang, Luyong Zhang, Zheng Li

{"title":"Discovery of P11–2: A Potent First-in-Class MNK1-Targeting PROTAC Degrader for the Treatment of Cancer","authors":"Zhongcheng Yang, Yuxia Liu, Zibin Liao, Lianru Chen, Zhiling Liang, Luyong Zhang, Zheng Li","doi":"10.1021/acs.jmedchem.5c00062","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00062","url":null,"abstract":"MAPK-interacting kinases (MNKs) are the only known kinases that phosphorylate eIF4E at Ser209, playing a critical role in tumor progression. However, the current MNK inhibitors have been limited due to the deficiency of effectiveness. Herein, we reported the design of the first-in-class MNK1-targeting PROTACs based on the MNK1 inhibitor DS12881479. Among them, P11–2 exhibited robust antitumor activity against MV4–11 cells (IC50 = 45 nM) by efficiently degrading MNK1 (DC50 = 11.92 nM, Dmax > 96%) mediated by the ubiquitin-proteasome system. Notably, P11–2 does not degrade MNK2, which played an important role in maintaining normal function. Moreover, P11–2 significantly suppressed the phosphorylation of eIF4E (IC50 = 22.07 nM), induced apoptosis, and arrested the cell cycle at the G1 phase. In addition, P11–2 exhibited favorable PK profiles and robust antitumor effects in the xenograft model. These findings highlight the potential of P11–2 as a novel therapeutic strategy for targeting the degradation of MNK1.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920583","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

A Perspective on the Strategic Application of Deconstruction–Reconstruction in Drug Discovery 解构-重构在药物发现中的策略性应用展望

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-05 DOI: 10.1021/acs.jmedchem.5c00036

J. Henry Blackwell, Iacovos N. Michaelides, Floriane Gibault

引用次数: 0

In Silico Design and Evaluation of Novel Peptide-Based PET Probe for Noninvasive Imaging of HER2 Expression in Breast Cancer 基于肽的新型PET探针在乳腺癌中HER2无创成像的芯片设计与评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-05 DOI: 10.1021/acs.jmedchem.5c00760

Xu Guo, Chunwei Xu, Xue Zhu, Xiaojia Wang, Yue Hao, Xun Wang, Ying Yao, Jing Fang, Ke Wang

{"title":"In Silico Design and Evaluation of Novel Peptide-Based PET Probe for Noninvasive Imaging of HER2 Expression in Breast Cancer","authors":"Xu Guo, Chunwei Xu, Xue Zhu, Xiaojia Wang, Yue Hao, Xun Wang, Ying Yao, Jing Fang, Ke Wang","doi":"10.1021/acs.jmedchem.5c00760","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00760","url":null,"abstract":"The overexpression of HER2 has been strongly correlated with the pathogenesis and progression of breast cancer. Developing HER2-targeted PET tracers for noninvasive assessment of HER2 expression holds substantial clinical significance for screening patients suitable for HER2-targeted therapy, evaluating treatment efforts, and optimizing treatment. In this study, we employed computational simulation methods to develop peptide WC8 derived from trastuzumab, and designed HER2 targeting radiotracers [68Ga]Ga-DOTA-WC8 for detecting the HER2 expression. The radiotracer demonstrated nanomolar affinity, high specificity, and favorable pharmacokinetics. PET imaging revealed that [68Ga]Ga-DOTA-WC8 exhibited significant and specific uptake in HER2-positive breast cancer tissues, facilitating the rapid and accurate identification of HER2 expression. Notably, this radiotracer was successfully utilized to achieve direct visualization of tumor response to pyrotinib, a HER2 tyrosine kinase inhibitor. These findings suggest that the peptide-based radiotracer [68Ga]Ga-DOTA-WC8 represents a promising tool for accurately monitoring of HER2 expression after treatment with HER2-targeting drugs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910529","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-Guided Optimization of 2-Aminoquinazoline Hematopoietic Progenitor Kinase 1 Inhibitors for Improved Oral Bioavailability and Synergistic Antitumor Immunity 结构导向优化2-氨基喹唑啉类造血祖激酶1抑制剂提高口服生物利用度和协同抗肿瘤免疫

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-05 DOI: 10.1021/acs.jmedchem.5c00762

Boheng Wan, Li Liang, Kaihong Zhong, Yiran Ma, Hui Wang, Ziang Wang, Shilong Sun, Tao Lu, Yadong Chen, Yong Zhu

{"title":"Structure-Guided Optimization of 2-Aminoquinazoline Hematopoietic Progenitor Kinase 1 Inhibitors for Improved Oral Bioavailability and Synergistic Antitumor Immunity","authors":"Boheng Wan, Li Liang, Kaihong Zhong, Yiran Ma, Hui Wang, Ziang Wang, Shilong Sun, Tao Lu, Yadong Chen, Yong Zhu","doi":"10.1021/acs.jmedchem.5c00762","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00762","url":null,"abstract":"Hematopoietic progenitor kinase 1 (HPK1), a pivotal T-cell immunity suppressor, offers transformative potential to overcome immune checkpoint resistance, yet existing inhibitors fail to balance potency, selectivity, and pharmacokinetics. We developed a spatially resolved strategy within a unified chemical framework of our 2-aminoquinazoline core, integrating (1) high-affinity engagement of the HPK1 hinge-region subpocket (Leu23/Phe93/Gly95) through bidentate hydrogen bonding and hydrophobic packing with (2) strategic occupation of a solvent-exposed allosteric site to sterically block CYP3A4/2C9/2D6-mediated oxidative metabolism. Optimized compound 39 demonstrated subnanomolar binding affinity (IC50 = 0.70 nM) with moderate selectivity, combined with high metabolic stability in human liver microsomes (CLint < 1 mL/min/kg) and favorable oral bioavailability (>100%) in mice. In CT26 models, compound 39 synergized with anti-PD-1 (60% tumor growth inhibition) by expanding IFN-γ+CD8+ tumor-infiltrating lymphocytes (7-fold) and enhancing splenic IFN-γ production (3-fold). This work validates 2-aminoquinazolines as a novel HPK1 chemotype addressing metabolic instability─a key hurdle in kinase drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910902","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

Pyrazolo[1,5-a]pyrimidine-Based Type-I Photosensitizer as an Efficient Pyroptosis Inducer for Tumor Ablation 基于吡唑啉[1,5-a]嘧啶的i型光敏剂作为肿瘤消融的有效热凋亡诱导剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-04 DOI: 10.1021/acs.jmedchem.4c03075

Shuo Zhang, Jingru Qiu, Hao Zhang, Baolan Chen, Xinke Zhang, Donghai Li, Guiling Li, Gang Shan

引用次数: 0

Discovery of Novel Cyclic Peptides as SMAD2–SMAD4 Interaction Inhibitors for the Treatment of Hepatic Fibrosis 发现新的环肽作为治疗肝纤维化的SMAD2-SMAD4相互作用抑制剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-04 DOI: 10.1021/acs.jmedchem.4c02938

Wei Cheng, Yawen Zheng, Qinglin Tang, Liang Qi, Zihan Shi, Qihong Yu, Mingmin Li, Xianzhi Wei, Yifeng Zhou, Xianxing Jiang

{"title":"Discovery of Novel Cyclic Peptides as SMAD2–SMAD4 Interaction Inhibitors for the Treatment of Hepatic Fibrosis","authors":"Wei Cheng, Yawen Zheng, Qinglin Tang, Liang Qi, Zihan Shi, Qihong Yu, Mingmin Li, Xianzhi Wei, Yifeng Zhou, Xianxing Jiang","doi":"10.1021/acs.jmedchem.4c02938","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02938","url":null,"abstract":"Hepatic fibrosis, characterized by the excessive deposition of the extracellular matrix, represents a common consequence of various chronic liver disorders. However, no specific drugs are available for antifibrotic therapy to date. SMAD2 is phosphorylated by transforming growth factor-β and subsequently binds to SMAD4 to generate a heteromeric complex, which then translocates into the nucleus and aggravates liver fibrosis. Herein, based on molecular docking simulation and structure–activity relationship study, we report the discovery of a novel cyclic peptide CMF9 that targets SMAD2 and potently interferes with the SMAD2–SMAD4 interaction. The subsequent in vivo and in vitro pharmacological studies demonstrated that CMF9 dramatically suppressed hepatic stellate cells activation and collagen synthesis, alleviating CCl4-induced hepatic inflammation and fibrosis. Overall, we first demonstrated that the novel cyclic peptide CMF9 could efficiently block the SMAD2–SMAD4 interaction via selectively inhibiting SMAD2 phosphorylation, providing a promising therapeutic strategy for targeting SMAD2 and an alternative candidate for the treatment of liver fibrosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910327","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 a New Class of Orexin 2 Receptor Agonists as a Potential Treatment for Narcolepsy 一类新的食欲素2受体激动剂作为治疗发作性睡的潜在药物的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-04 DOI: 10.1021/acs.jmedchem.5c00362

Davide Pozzi, Romain Siegrist, Jens-Uwe Peters, Christopher Kohl, Andreas Mühlemann, Simon Schlienger, Caterina Torrisi, Eleanor Lindenberg, Melanie Kessler, Catherine Roch

{"title":"Discovery of a New Class of Orexin 2 Receptor Agonists as a Potential Treatment for Narcolepsy","authors":"Davide Pozzi, Romain Siegrist, Jens-Uwe Peters, Christopher Kohl, Andreas Mühlemann, Simon Schlienger, Caterina Torrisi, Eleanor Lindenberg, Melanie Kessler, Catherine Roch","doi":"10.1021/acs.jmedchem.5c00362","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00362","url":null,"abstract":"The orexinergic system, projecting from the lateral hypothalamus, operates through two receptors, orexin receptor type-1 (OX1) and orexin receptor type-2 (OX2), stabilizing wakefulness, mainly via OX2. Narcolepsy Type 1 (NT1) is characterized by excessive sleepiness and cataplexy, and is linked to a loss of orexin-producing neurons. Current therapies manage the symptoms but do not address the underlying cause of the disease. For example, psychostimulants (e.g., modafinil) reduce excessive daytime sleepiness (EDS) and sodium oxybate (gammaaminobutyric acid receptor agonist) reduces both EDS and cataplexy. Despite decades of research, no small-molecule OX2 agonist has reached the market. This study presents the discovery of two new brain-penetrant, orally bioavailable OX2 agonists with a phenylglycine-like scaffold. These compounds stabilized wakefulness and reduced cataplexy in a mouse model of NT1. In healthy dogs, they increased time in wakefulness. These results highlight their potential as treatment for narcolepsy and other types of hypersomnolence.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910329","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

AI-Driven De Novo Design and Development of Nontoxic DYRK1A Inhibitors ai驱动的无毒DYRK1A抑制剂的从头设计和开发

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-03 DOI: 10.1021/acs.jmedchem.5c00512

Eduardo González García, Pablo Varas, Pedro González-Naranjo, Eugenia Ulzurrun, Guillermo Marcos-Ayuso, Concepción Pérez, Juan A. Páez, David Rios Insua, Simón Rodríguez Santana, Nuria E. Campillo

{"title":"AI-Driven De Novo Design and Development of Nontoxic DYRK1A Inhibitors","authors":"Eduardo González García, Pablo Varas, Pedro González-Naranjo, Eugenia Ulzurrun, Guillermo Marcos-Ayuso, Concepción Pérez, Juan A. Páez, David Rios Insua, Simón Rodríguez Santana, Nuria E. Campillo","doi":"10.1021/acs.jmedchem.5c00512","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00512","url":null,"abstract":"Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is implicated in several human diseases, including DYRK1A syndrome, cancer, and neurodegenerative disorders such as Alzheimer’s disease, making it a relevant therapeutic target. In this study, we combine artificial intelligence with traditional drug discovery methods to design nontoxic DYRK1A inhibitors. An ensemble QSAR model was used to predict binding affinities, while a directed message passing neural network evaluated toxicity. Novel compounds were generated using a hierarchical graph-based generative model and subsequently refined through molecular docking, chemical synthesis, and experimental validation. This pipeline led to the identification of pyrazolyl-1H-pyrrolo[2,3-b]pyridine 1 as a potent inhibitor, from which a new derivative series was developed. Enzymatic assays confirmed nanomolar DYRK1A inhibition, and additional assays demonstrated antioxidant and anti-inflammatory properties. Overall, the resulting compounds exhibit strong DYRK1A inhibition and favorable pharmacological profiles.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"109 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903004","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

Design, Synthesis, and Biological Evaluation of Novel Activators of Human Caseinolytic Protease P with a Pyrazololactam Scaffold 吡唑内酰胺支架的新型人酪蛋白水解蛋白酶P激活剂的设计、合成和生物学评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-03 DOI: 10.1021/acs.jmedchem.4c03000

Rui Tang, Qiannan Li, Heyang Zhou, Yu Li, Tong Li, Jinxin Jiang, Ziyuan Chen, Lingmei Kong, Yan Li, Yibei Xiao, Haiying Sun

引用次数: 0

Design, Synthesis, and Evaluation of a Novel Positron Emission Tomography Tracer Targeting Fibroblast Activation Protein: From Bench to Bedside 针对成纤维细胞活化蛋白的新型正电子发射断层扫描示踪剂的设计、合成和评价：从实验室到床边

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-02 DOI: 10.1021/acs.jmedchem.4c02961

Ganghua Tang, Rongqin Zhang, Xiaojun Zhang, KeYin Chen, Fengping Gong, Yanchao Huang, Zhanwen Zhang, Jiawen Huang

{"title":"Design, Synthesis, and Evaluation of a Novel Positron Emission Tomography Tracer Targeting Fibroblast Activation Protein: From Bench to Bedside","authors":"Ganghua Tang, Rongqin Zhang, Xiaojun Zhang, KeYin Chen, Fengping Gong, Yanchao Huang, Zhanwen Zhang, Jiawen Huang","doi":"10.1021/acs.jmedchem.4c02961","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02961","url":null,"abstract":"FAPI-PET/CT has become a promising tool for cancer diagnosis. However, the pharmacokinetic properties of FAPI tracers need optimization. Here, we developed a novel FAPI tracer, [18F]AlF-NOTA-SP2A-FAPT, for cancer imaging. NOTA-SP2A-FAPT was successfully synthesized and radiolabeled with a high radiochemical purity. [18F]AlF-NOTA-SP2A-FAPT displayed satisfying stability, hydrophilicity, and affinity to FAP, as well as specific uptake in A549-FAP cells. Micro-PET/CT showed that [18F]AlF-NOTA-SP2A-FAPT is rapidly excreted through the renal system. [18F]AlF-NOTA-SP2A-FAPT exhibited high tumor uptake and excellent retention, showing better tumor delineation compared to [18F]FDG and [18F]AlF-NOTA-FAPI-42. Pilot clinical studies of [18F]AlF-NOTA-SP2A-FAPT and head-to-head comparison with [18F]FDG were performed on 13 cancer patients. Compared to [18F]FDG, [18F]AlF-NOTA-SP2A-FAPT had higher uptake in primary tumor and lymph node metastases as well as favorable distribution and good tumor retention. In conclusion, [18F]AlF-NOTA-SP2A-FAPT demonstrated high tumor accumulation, as well as improved pharmacokinetic properties. [18F]AlF-NOTA-SP2A-FAPT could emerge as a promising alternative to the currently established FAPI tracers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901258","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