Journal of Medicinal Chemistry最新文献

{"title":"Drug Discovery and Development Faces an Ominous Future from NIH Indirect Costs Rate Cuts","authors":"David E. Heppner","doi":"10.1021/acs.jmedchem.5c00444","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00444","url":null,"abstract":"On February 7, 2025, the Office of the Director of the National Institutes of Health (NIH) issued a Supplemental Guidance to the 2024 NIH Grants Policy Statement, stating: “For all existing grants to [Institutions of Higher Education], retroactive to the date of issuance of this Supplemental Guidance, award recipients are subject to a 15 percent indirect cost rate.” (1) This reduction in the indirect cost (IDC) rate is a considerable cut in financial support for critical overhead and administrative expenses that are essential for health research. Specifically, IDCs are used for facilities such as laboratory space, scientific instruments, research computing infrastructure, safety and regulatory compliance, research core operations, and support staff. They also play a crucial role in sustaining research institutions, and such drastic cuts could lead to the loss of hundreds of millions of dollars for NIH-funded institutions. The implications are profound, threatening to disrupt a wide spectrum of biomedical research, from basic laboratory investigations to clinical trials. Furthermore, the abrupt nature of these cuts leaves institutions with little time to adjust, placing them in immediate financial distress. The medicinal chemistry community, in particular, will face significant setbacks. NIH-funded academic institutions serve as hubs for early stage drug discovery research, identifying novel drug targets and pioneering new chemical entities that may ultimately become transformative therapeutics. The pathway from discovery to market often depends on academic institutions partnering with industry collaborations that facilitate clinical trials and the path toward regulatory approval showing how these cuts will have impacts beyond. While the full impact of these IDC rate reductions remains uncertain, it is evident that they will slow the drug development pipeline, increasing both the time and difficulty of bringing new medicines to patients. At this juncture, it remains unclear how best to navigate these policy changes, despite lawsuits filed and a temporary restraining order. (2,3) Previous funding decisions have already contributed to widespread uncertainty, and further budgetary constraints are likely to exacerbate these challenges. However, drug discovery has long been recognized as a “team sport”, (4) bringing people together in a singular, multidisciplinary workforce dedicated to translating fundamental research into life-changing treatments. In response to these financial constraints, our research community must advocate for resilient support of biomedical research. This includes securing the necessary funding to promote groundbreaking science and fostering the next generation of scientists through robust educational and training programs. Now, more than ever, we must be united to ensure that scientific progress continues unimpeded and that the discovery and development of life-saving therapies remain a national priority. D.E.H. acknowledges ge","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452067","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}

{"title":"Turning Off STAT6 with a Targeted Degrader","authors":"Dehua Pei","doi":"10.1021/acs.jmedchem.5c00415","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00415","url":null,"abstract":"While an attractive target for treating a range of human diseases and conditions, signal transducer and activator of transcription 6 (STAT6) has resisted drug discovery efforts for decades. This Viewpoint summarizes the discovery of a highly potent, selective STAT6 degrader with minimal off-target activity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462702","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}

{"title":"Design, Synthesis, and Biological Evaluation of Novel Fms-Like Tyrosine Kinase 3/VEGFR2/Histone Deacetylase Inhibitors for the Treatment of Acute Myeloid Leukemia","authors":"Hua Tian, Yichen Liu, Songwen Lin, Jialing Deng, Qinghua Zhang, Feng Hao, Yao Tang, Tianning Xiong, Kehui Zhang, Ge Shi, Lijun Luo, Shouguo Peng, Li Sheng, Ming Ji, Heng Xu","doi":"10.1021/acs.jmedchem.4c03084","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03084","url":null,"abstract":"The concurrent targeting of Fms-like tyrosine kinase 3 (FLT3)/VEGFR2/Histone deacetylase (HDAC) represents a novel and promising therapeutic strategy for acute myeloid leukemia. In this work, we hybridized essential pharmacophores from sorafenib and SAHA (vorinostat) and then conducted structure–activity relationship studies to identify two lead compounds <b>26</b> and <b>32</b> that potently inhibit FLT3, VEGFR2, and HDAC in a nanomolar range. In cell evaluation, compounds <b>26</b> and <b>32</b> exhibited potent proliferative activities against a panel of leukemia cells including MV4-11 and MOLM-13. Western blotting analysis also showed that compounds <b>26</b> and <b>32</b> suppressed the phosphorylation of FLT3, STAT3, and ERK1/2 and increased histone H3 acetylation in a dose-dependent manner, indicating the effective inhibition of FLT3, VEGFR2, and HDAC. Supported by its pharmacokinetic properties, compound <b>26</b> showed remarkable anticancer efficacy in a MV4-11 xenograft model. Additionally, it demonstrated superior efficacy compared to midostaurin and gilteritinib in the Ba/F3-FLT3-ITD-N701K xenograft model.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"130 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451807","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}

{"title":"Dual-Targeting TrxR-EGFR Alkynyl-Au(I) Gefitinib Complex Induces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradation of GPX4.","authors":"Lingling Wang, Xiaoyan Ma, Ling Zhou, Miao Luo, Yunlong Lu, Yawen Wang, Pengdou Zheng, Huiguo Liu, Xiansheng Liu, Wukun Liu, Shuang Wei","doi":"10.1021/acs.jmedchem.4c02252","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02252","url":null,"abstract":"<p><p>Gefitinib exhibits significant clinical efficacy in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) sensitive mutations. However, its efficacy is severely limited by acquired resistance. Herein, we designed and synthesized a series of dual-targeting thioredoxin reductase (TrxR)-EGFR gold complexes by attaching a gold ligand to the parent structure of gefitinib, 4-anilinoquinazoline. Among them, <b>L1Au2</b> exhibited significant activity against both gefitinib-sensitive and resistant lung cancers, effectively inhibiting tumor proliferation and promoting apoptosis. Mechanistically, <b>L1Au2</b> effectively inhibits TrxR and EGFR both in vitro and in vivo. Additionally, <b>L1Au2</b> promotes the degradation of GPX4 protein via autophagolysosomal and proteasomal pathways, leading to ferroptosis. Notably, <b>L1Au2</b> also induces endoplasmic reticulum stress (ERS) and triggers immunogenic cell death (ICD). In conclusion, this study provides an innovative strategy for overcoming gefitinib resistance in lung cancer by utilizing dual-targeting TrxR-EGFR alkynyl-Au(I) gefitinib derivatives, thereby offering a new approach for treating gefitinib-resistant lung cancer.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447391","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}

{"title":"Structure-Based Discovery of a Highly Selective, Oral Polo-Like Kinase 1 Inhibitor with Potent Antileukemic Activity.","authors":"Jianyu Nie, Xiaojiao Sun, Yan He, Mingxin Zhu, Xinglong Zhang, Qin Wang, Zhenming Liu, Zhouling Xie, Zhongtang Li, Chenzhong Liao","doi":"10.1021/acs.jmedchem.4c02422","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02422","url":null,"abstract":"<p><p>Polo-like kinase 1 (PLK1) plays pivotal roles in cell division and cancer pathogenesis, making it a highly coveted therapeutic target for anticancer strategies. This article reports a series of PLK1 inhibitors developed using a structure-based strategy, culminating in the discovery of compound <b>B31</b>, a novel isoform-specific PLK1 inhibitor with excellent kinome selectivity. <i>In vitro</i>, this compound exhibited superior anticancer potency across a broad spectrum of cell lines, particularly against K562, achieving a remarkable IC₅₀ value of 0.08 nM. In a mouse model harboring subcutaneous K562 tumors, oral administration of <b>B31</b> at dosages of 10 or 20 mg/kg twice weekly exhibited remarkable antileukemic activity. <b>B31</b> had minimal impact on HEK293T cells and very weak inhibitory activity against the hERG channel. Furthermore, in the acute toxicity test, this compound demonstrated an extraordinary safety profile even at a dosage of 500 mg/kg, highlighting its potential as a novel antileukemic agent.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447397","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}

{"title":"An 211At-labeled Tetrazine for Pretargeted Therapy","authors":"Matthias M. Herth, Lars Hvass, Christian B. M. Poulie, Marius Müller, Rocio García-Vázquez, Tobias Karl Gustavsson, Vladimir Shalgunov, Anne S. Clausen, Jesper T. Jørgensen, Ellinor Hansson, Holger Jensen, Emma Aneheim, Sture Lindegren, Andreas Kjaer, Umberto M. Battisti","doi":"10.1021/acs.jmedchem.4c02281","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02281","url":null,"abstract":"Pretargeted radioimmunoimaging has been shown to enhance tumor-to-background ratios by up to 125-fold at early time points, leading to more efficient and less toxic radionuclide therapies, particularly with shorter half-lives such as astatine-211 (²¹¹At). The tetrazine ligation is the most utilized bioorthogonal reaction in these strategies, making tetrazines ideal for ²¹¹At labeling and controlling the biodistribution. We developed a ²¹¹At-labeled pretargeting agent for alpha-radionuclide therapy, achieving a radiochemical yield of approximately 65% and purity over 99%. Our results showed higher tumor-to-blood ratios within the first 24 h compared to directly labeled monoclonal antibodies. This suggests that pretargeted therapy may deliver better tumor doses than conventional methods, although the deastatination observed will need to be addressed in future tetrazine developments.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435513","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}

{"title":"One-Pot Synthesis of Novel Tetrasubstituted α-Aminophosphonates Derived from α-Methylphosphoserine and In Vivo Evaluation as Anti-Inflammatory Agents","authors":"Misael López-Castillo, Mario Ordóñez, Itzel Bernal-Evangelista, Gil A. Vázquez-Arredondo, Martha Vanessa Gutiérrez-Baños, Ivan Romero-Estudillo, Gabriela Castañeda-Corral","doi":"10.1021/acs.jmedchem.4c02496","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02496","url":null,"abstract":"A series of new tetrasubstituted α-aminophosphonate derivatives with a methylphosphoserine fragment were described. These compounds were synthesized by a three-component (3-CR) “Kabachnik-Fields reaction.” The novel α-aminophosphonates were screened for <i>in vivo</i> anti-inflammatory activity through topical and oral administration routes. All compounds decreased TPA-induced ear edema in a dose-dependent fashion. In this test, compounds <b>2</b>, <b>5,</b> and <b>7</b> showed the same efficacy (≈ 90%) and higher potency than indomethacin and decreased the inflammatory marker neutrophil-to-lymphocyte ratio (NLR). Moreover, oral pretreatment and post-treatment with compounds <b>2</b>–<b>7</b> reduced CFA-induced paw edema, as did indomethacin or (<i>S</i>)-naproxen. Based on the promising <i>in vivo</i> anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles <i>in silico</i>. The analysis also revealed that the novel tetrasubstituted α-aminophosphonates did not break Lipinski’s rule of five and had drug-likeness and favorable ADME properties for oral and transdermal administration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435514","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}

{"title":"Conformational Role of Methyl in the Potency of Cyclohexane-Substituted Squaramide CCR6 Antagonists","authors":"Brian S. Gerstenberger, Ray Unwalla, Kathleen A. Farley, Philippe Nuhant, Vincent M. Lombardo, Wei Li, Kimberly Crouse, Richard K. Frisbie, Eric P. Arnold, Mark W. Bundesmann, Gary M. Chinigo, Andrew Flick, Neelu Kaila, Daniel Lamb, James J. Mousseau, Nootaree Niljianskul, Mathieu Rappas, John I. Trujillo, Michael L. Vazquez, Atli Thorarensen, Mark E. Schnute","doi":"10.1021/acs.jmedchem.4c03106","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03106","url":null,"abstract":"CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6⁺ T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the <i>cis</i>-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427368","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}

{"title":"Opening the Door to a New Treatment Paradigm: The Re-emergence of Chymase Inhibitors","authors":"Franz von Nussbaum, Giambattista Testolin","doi":"10.1021/acs.jmedchem.5c00413","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00413","url":null,"abstract":"Chymase is a serine protease that has been studied as a drug target in inflammatory diseases, so far with limited success. Fulacimstat is a novel drug candidate inhibiting chymase that has been investigated in clinical trials for the role of chymase in inflammation. Despite a good safety profile, further clinical development of fulacimstat was not pursued due to a lack of efficacy. Recently, a new role of chymase in blood clot biology has been identified, this resparks interest in chymase inhibitors, and positions fulacimstat as a potential innovative option to treat thrombotic conditions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435516","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}

{"title":"Opto-Epigenetic Regulation of Histone Arginine Asymmetric Dimethylation via Type I Protein Arginine Methyltransferase Inhibition","authors":"Shuting Xu, Kaiqi Long, Tianyi Wang, Yangyang Zhu, Yunjiao Zhang, Weiping Wang","doi":"10.1021/acs.jmedchem.4c02199","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02199","url":null,"abstract":"Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435515","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}