European Journal of Medicinal Chemistry最新文献

{"title":"Discovery of an orally bioavailable pyridone-based BRD4 inhibitor with potent antitumor efficacy in colorectal cancer","authors":"Zhangyun Fang ,&nbsp;Shuai Zhan ,&nbsp;Churu Mao ,&nbsp;Ningjing Zhang ,&nbsp;Xiaofeng Zhao ,&nbsp;Yun Huang ,&nbsp;Wanjing Ding ,&nbsp;Zhongjun Ma","doi":"10.1016/j.ejmech.2026.118573","DOIUrl":"10.1016/j.ejmech.2026.118573","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a major clinical burden with limited durable responses. Given reports implicating Bromodomain-containing protein 4 (BRD4) in CRC proliferation and therapy resistance, more potent BRD4-targeting agents with proven <em>in-vivo</em> activity are needed. Through virtual screening followed by structure-guided chemical modification, we identified <strong>H5</strong> as a BRD4 inhibitor. In biochemical assays, <strong>H5</strong> shows IC₅₀ = 7.9 ± 0.5 nM, outperforming <strong>JQ-1</strong> (IC₅₀ = 33.0 ± 1.0 nM) by 4-fold. Molecular dynamics simulations indicate that <strong>H5</strong> engages BRD4 <em>via</em> hydrogen bonds with Asn140 and Asp88 and a water-mediated bridge to Gln85. In the HCT-116 xenograft mouse model, oral administration of <strong>H5</strong> suppressed tumor growth (TGI = 82 % at 50 mg/kg) and downregulated the BRD4-driven oncoproteins c-MYC and BCL-2. Collectively, <strong>H5</strong> emerges as a highly promising BRD4-targeted candidate for colorectal cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118573"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current landscape and therapeutic prospects of indole hybrids for prostate cancer treatment: A mini-review","authors":"Zhi Xu,&nbsp;Yang Shi,&nbsp;Bowen Pan,&nbsp;Huabin Wang","doi":"10.1016/j.ejmech.2026.118583","DOIUrl":"10.1016/j.ejmech.2026.118583","url":null,"abstract":"<div><div>Prostate cancer ranks second in incidence and fifth in mortality among all cancer types in males. This striking epidemiological profile highlights its status as a major health concern that poses a severe threat to men's lives and health globally. Although traditional chemotherapeutics and targeted therapies for prostate cancer have made considerable progress, critical challenges remain, including high metastatic potential, acquired drug resistance, and unfavorable prognosis in patients with advanced disease, highlighting the imperative to develop novel therapeutic strategies. Indole hybrids, versatile and promising anticancer scaffolds formed by integrating indole moieties with other pharmacophores, exhibit prominent multi-targeted regulatory capabilities in prostate cancer therapy, enabling simultaneous modulation of key oncogenic pathways to address the complex molecular mechanisms of both hormone-sensitive and castration-resistant subtypes. Compared to single-scaffold derivatives, indole hybrids demonstrate enhanced anticancer potency and reduced off-target toxicity <em>via</em> synergistic effects between conjugated moieties, while also showing potential in overcoming drug resistance by circumventing single-target mutation-induced resistance and inhibiting ABC transporters to reverse multidrug resistance. Moreover, their structural flexibility facilitates structural optimization for improved pharmacokinetic properties and tailored efficacy against specific prostate cancer phenotypes, making indole hybrids valuable candidates for developing novel therapeutic agents to meet unmet clinical needs in prostate cancer treatment. This review summarizes the recent advances in indole hybrids with anti-prostate cancer activity from 2021 to date, striving to open new directions for developing novel prostate cancer therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118583"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent progress of napabucasin as privileged scaffold in the discovery of anticancer agents","authors":"Xiaojuan Yang ,&nbsp;Guoyang Ma","doi":"10.1016/j.ejmech.2026.118559","DOIUrl":"10.1016/j.ejmech.2026.118559","url":null,"abstract":"<div><div>Cancer is a major health issue worldwide, necessitating the development of novel treatments because treating this disease is challenging. Napabucasin, a furan-fused 1,4-naphthoquinone, exhibits significant anticancer activity through various molecular mechanisms and has become a privileged scaffold for developing antitumor therapeutics. In this review, we systematically evaluated recent progress in the use of napabucasin as a privileged scaffold for the discovery of antitumor drugs, focusing on structure-activity relationships (SARs), structural modification strategies, and the illustration of tumor inhibitory pathways from a mechanistic perspective. By conducting multidimensional assessments, we propose feasible directions for developing napabucasins with improved pharmacological properties for cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118559"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computer-Aided optimization of quinazoline-based Aurora kinase inhibitors for enhanced metabolic stability","authors":"Song Chen ,&nbsp;Hongjin Zhai ,&nbsp;Shuhan You,&nbsp;Bin Zhang,&nbsp;Gui Lu","doi":"10.1016/j.ejmech.2025.118548","DOIUrl":"10.1016/j.ejmech.2025.118548","url":null,"abstract":"<div><div>The quinazoline-based Aurora kinase inhibitor <strong>9h</strong>, previously developed by our group, exhibited potent efficacy both <em>in vitro</em> and <em>in vivo</em>. However, its further development was hindered by a short half-life and insufficient metabolic stability. To address these limitations, we employed machine learning-driven <em>in silico</em> models to predict <strong>9h</strong>′s key metabolic sites. Based on these predictions, electronic isosteric substitutions and metabolic blocking strategies were employed to optimize these sites, yielding a series of new quinazoline derivatives. Subsequent liver microsomal stability assays identified compound <strong>4q</strong> as the lead candidate, exhibiting significantly enhanced metabolic stability with a 14-fold and 4.5-fold increase in half-life relative to <strong>9h</strong> in rat and human microsomes, respectively. Pharmacokinetic evaluation in rats revealed <strong>4q</strong> possesses a favorable profile, with an oral half-life of 5.5 h, an intravenous half-life of 4.1 h, and an oral bioavailability of 58 %. Importantly, <strong>4q</strong> maintained potent inhibitory activity <em>in vivo</em>, achieving a tumor growth inhibition rate of 56.7 %, consistent with its robust <em>in vitro</em> efficacy. Molecular docking simulations further elucidated <strong>4q</strong>′s binding mode with Aurora kinase, providing a structural basis for its activity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118548"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fragment-based structure-activity relationship analysis of CK-571 reveals non-interacting groups drive smooth muscle myosin selectivity","authors":"Sharad Kumar Suthar ,&nbsp;Tamás Jernei ,&nbsp;Csilla Kurdi ,&nbsp;Ádam I. Horváth ,&nbsp;Anna Ágnes Rauscher ,&nbsp;Máté Gyimesi ,&nbsp;András Málnási-Csizmadia","doi":"10.1016/j.ejmech.2025.118476","DOIUrl":"10.1016/j.ejmech.2025.118476","url":null,"abstract":"<div><div>Smooth muscle myosin-2 (SMM) is a promising target for treating asthma and COPD, but selective inhibition remains challenging due to the high conservation of myosin-2 isoforms. CK-571 is the first potent and selective SMM inhibitor, despite binding to an allosteric site conserved across isoforms. We performed a fragment-based structure–activity relationship analysis to deconstruct CK-571 and define the role of each segment. The isoquinoline-carbamate and chloro-fluorobenzyl moieties were found to be inactive when isolated. Surprisingly, the presence of a methyl group and a solvent-exposed pair of non-interacting dihydroxyl groups dramatically enhanced potency by up to 100-fold, despite no direct contact with the protein. These findings highlight the critical contribution of non-interacting, flexible groups in optimizing ligand potency and selectivity for conserved targets and establish a framework for the development of improved SMM-targeted therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118476"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design of an NLRP3 inhibitor with superior efficacy and safety for gout therapy","authors":"Yichao Kong ,&nbsp;Mengjun Su ,&nbsp;Caihong Jiang ,&nbsp;Haonan Feng ,&nbsp;Yingjie Hu ,&nbsp;Donglai Li ,&nbsp;Zhenyu Mao ,&nbsp;Fengling Liu ,&nbsp;Fuli Zhu ,&nbsp;Yue Guo ,&nbsp;Shuhua Ren ,&nbsp;Man Chi ,&nbsp;Ting Qiu ,&nbsp;Yaxia Yuan ,&nbsp;Weiwei Huang ,&nbsp;Lei Ma ,&nbsp;Xiabin Chen","doi":"10.1016/j.ejmech.2026.118578","DOIUrl":"10.1016/j.ejmech.2026.118578","url":null,"abstract":"<div><div>Gout, driven by urate crystal-induced inflammation, remains a therapeutic challenge due to the limited efficacy and toxicity of current treatments. Targeting the NLRP3 inflammasome, a central driver of gout pathogenesis, offers a promising strategy. While MCC950, a potent NLRP3 inhibitor, demonstrated clinical potential, its discontinuation due to hepatotoxicity underscores the urgent need for safer alternatives. Here, we address these challenges through a rational drug design approach to develop next-generation NLRP3 inhibitors. By leveraging cryo-EM structures and molecular dynamics (MD) simulations of the MCC950-NLRP3 complex, we identified a structurally dynamic region near the furan moiety and an adjacent unoccupied hydrophobic pocket. Systematic structural optimization targeting this pocket enabled the design of <strong>M48</strong>, a derivative that exhibited superior anti-inflammatory activity (IC₅₀ = 11.9 nM), favorable oral bioavailability (89.7 % in rats), and an improved safety profile compared to MCC950. In an MSU-induced mouse gout model, <strong>M48</strong> demonstrates superior anti-inflammatory and analgesic effects compared to indomethacin, with efficacy comparable to colchicine. The design strategy, grounded in computational insights into ligand-protein interactions, demonstrates both scientific rigor and broad applicability for optimizing small-molecule inhibitors. Notably, <strong>M48</strong>'s enhanced efficacy and reduced liver toxicity risk validate the approach's potential for addressing unmet clinical needs in gout and other NLRP3-associated diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118578"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations","authors":"Dongping Yao ,&nbsp;Ni Zhang ,&nbsp;Qian Yao ,&nbsp;Yongmei Xie ,&nbsp;Rong Tian ,&nbsp;Xiaoai Wu ,&nbsp;Weihong Kuang","doi":"10.1016/j.ejmech.2025.118542","DOIUrl":"10.1016/j.ejmech.2025.118542","url":null,"abstract":"<div><div>Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-<em>a</em>]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound <strong>28</strong>, which showed high affinity with tau aggregates (<em>K</em>_<em>i</em> = 0.99 nM). Compound <strong>28</strong> also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct S_NAr radiofluorination, ¹⁸F-<strong>28</strong> was successfully produced with high radiochemical yield. <em>In vitro</em> stability tests and log <em>D</em>_<em>7.4</em> measurement indicated ¹⁸F-<strong>28</strong> hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and <em>in vivo</em> PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with ¹⁸F-<strong>28</strong> in normal mice and P301L transgenic mice, as well as a fast clearance from brain. ¹⁸F-<strong>28</strong> was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of ¹⁸F-<strong>28</strong> with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound <strong>28</strong> holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118542"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based virtual screening of ultra-large chemical spaces: Advances and pitfalls","authors":"François Sindt,&nbsp;Didier Rognan","doi":"10.1016/j.ejmech.2026.118576","DOIUrl":"10.1016/j.ejmech.2026.118576","url":null,"abstract":"<div><div>On-demand chemical spaces consist of molecules that are, <em>a priori</em>, readily synthesizable from sets of commercial building blocks through robust organic reactions. As these spaces expand—now reaching the scale of several trillions of compounds—computational chemists are compelled to develop innovative algorithms for efficient enumeration, storage, and virtual screening, particularly when three-dimensional constraints of target proteins are involved. This review examines the primary approaches to structure-based ultra-large virtual screening, highlighting the significant advantages of screening at such a scale while addressing the remaining practical and theoretical hurdles. Current prospective applications, often relying on brute-force docking, typically report improved hit rates and more potent primary hits; however, they must contend with the exponential growth of available chemical space. To address this, recent developments have integrated active learning, probabilistic sampling, and synthon-guided methods to accelerate docking and prioritize the most promising compounds. Finally, we provide a perspective on the transformative impact of ultra-large chemical spaces on early hit identification and the overall organization of early drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118576"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure function and design of polymyxins to enable safer and more potent anti Gram negative agents","authors":"Hassan Gamal ,&nbsp;Cesar Augusto Roque-Borda ,&nbsp;Beatriz G. de la Torre ,&nbsp;Fernando Albericio","doi":"10.1016/j.ejmech.2026.118575","DOIUrl":"10.1016/j.ejmech.2026.118575","url":null,"abstract":"<div><div>Polymyxins, particularly colistin, have re-emerged as last-line antibiotics against multidrug-resistant Gram-negative bacteria. Beyond their clinical revival, they represent a unique platform for medicinal chemistry, owing to their cyclic peptide scaffold, cationic diaminobutyric acid residues, and hydrophobic fatty acyl tail. Recent advances in solid-phase synthesis, structural biology, and molecular pharmacology have revealed critical structure–activity relationships (SAR) that govern antibacterial potency, toxicity, and resistance. This review highlights how chemical modification of Dab side chains, the N-terminal fatty acid, and the cyclic heptapeptide ring has led to next-generation analogues with improved efficacy and safety. We further discuss emerging synthetic strategies, mimetic design, and combination therapies that exploit polymyxin scaffolds to overcome resistance. These insights showcase polymyxins not merely as “old drugs” but as versatile chemical blueprints for innovative lipopeptide therapeutics targeting Gram-negative “superbugs”.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118575"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel aminopyrimidine-hydroxamate derivatives as dual FLT3/HDAC inhibitors: Design, synthesis, and anti-hematologic malignancy evaluation","authors":"Fansheng Ran ,&nbsp;Rong Cao ,&nbsp;Yifan Ma ,&nbsp;Dongliang Ji ,&nbsp;Tiantian Sun ,&nbsp;Mingming Chang ,&nbsp;Chen Chen ,&nbsp;Chunyu Yin ,&nbsp;Hongming Huang ,&nbsp;Yong Ling","doi":"10.1016/j.ejmech.2026.118574","DOIUrl":"10.1016/j.ejmech.2026.118574","url":null,"abstract":"<div><div>The constitutive activation of FMS-like tyrosine kinase 3 (FLT3) is closely associated with the progression of hematologic malignancies; however, the clinical application of FLT3 inhibitors has been limited by acquired drug resistance. Recent advances in epigenetic regulatory mechanisms revealed that aberrant histone deacetylase (HDAC) expression exacerbates resistance to FLT3 inhibitors through multiple signaling pathways. Accordingly, we designed and synthesized a series of aminopyrimidine-hydroxamate derivatives (<strong>6a-6s</strong>) as dual FLT3/HDAC inhibitors for the treatment of hematologic malignancies. The representative compound <strong>6s</strong> demonstrates superior dual-targeting properties, exhibiting 150-fold higher FLT3 inhibition (half-maximal inhibitory concentration (IC₅₀) = 14 nM) compared with the reference drug tandutinib (IC₅₀ = 2098 nM) and 2.9-fold higher HDAC1 inhibition (IC₅₀ = 27 nM) relative to vorinostat (SAHA; IC₅₀ = 79 nM). In the human acute myeloid leukemia MV-4-11 cell line, <strong>6s</strong> exhibits remarkable antiproliferative potency (IC₅₀ = 29 nM), outperforming the single-target inhibitors tandutinib (IC₅₀ = 7630 nM) and SAHA (IC₅₀ = 3760 nM) by 263- and 129-folds, respectively. Notably, <strong>6s</strong> shows marked efficacy in a human mantle cell lymphoma Jeko-1 model (IC₅₀ = 99 nM), indicating broad-spectrum therapeutic potential. Furthermore, <strong>6s</strong> exhibits remarkable kinase selectivity, plasma stability, and human hepatic microsomal metabolic stability. Importantly, in the Jeko-1 xenograft model, <strong>6s</strong> achieves 53.34 % tumor growth inhibition at a dose of 30 mg/kg with no observable toxicity. Collectively, these results indicate that <strong>6s</strong> is a potent dual FLT3/HDAC inhibitor with promising therapeutic potential for hematologic malignancies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118574"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}