European Journal of Medicinal Chemistry最新文献_第5页

Diversified design strategies for small-molecule PROTACs: How do we select? 小分子PROTACs的多样化设计策略：我们如何选择？

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-17 DOI: 10.1016/j.ejmech.2026.118593

Qing-Song Chen, Jian-Hua Liang

{"title":"Diversified design strategies for small-molecule PROTACs: How do we select?","authors":"Qing-Song Chen, Jian-Hua Liang","doi":"10.1016/j.ejmech.2026.118593","DOIUrl":"10.1016/j.ejmech.2026.118593","url":null,"abstract":"<div><div>Although PROTAC technology has revolutionized drug discovery by enabling the degradation of previously undruggable proteins, the clinical translation of traditional PROTACs has been hindered by limitations in E3 ligase availability, suboptimal drug-like properties, and a narrow target scope. In recent years, the emergence of diversified novel PROTAC design strategies, such as chaperone-mediated PROTAC (CHAMP), mini-PROTAC, covalent PROTAC, HyTTD, and pro-PROTAC, has elevated the technology to new heights, accelerating its clinical advancement. However, a critical question remains: How can we select the most appropriate strategy among these options? We summarized and analyzed their strengths and limitations, covering optimization and expansion of E3 ligase-dependent and E3 ligase-independent degrader strategies, undruggable targets degrader strategies, linker optimization and expansion strategies, and pro-PROTAC strategies. Furthermore, we provide guidance on selecting appropriate strategies based on specific target characteristics for designing effective PROTAC, with the aim of facilitating the translation of these innovative approaches toward clinical applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118593"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995780","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}

引用次数: 0

Structure-activity relationship of N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives as G-protein-biased KOR-selective agonists n-环丙基甲基-7α-（间甲基氨基苯基）-6,14-内乙醇-北啡衍生物作为g蛋白偏倚的kor选择性激动剂的构效关系

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-17 DOI: 10.1016/j.ejmech.2026.118591

Siyuan Tang , Jiangwen Gui , Yingjie Lan , Panwen Liu , Yuliang Lin , Meng Sun , Shaoliang Duan , Chao Zhang , Denggao Zhang , Min Liu , Xiaobo Mai , Jiaqi Tan , Zhiwen Wang , Jinggen Liu , Liming Shao , Wei Fu , Yujun Wang , Wei Li

{"title":"Structure-activity relationship of N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives as G-protein-biased KOR-selective agonists","authors":"Siyuan Tang , Jiangwen Gui , Yingjie Lan , Panwen Liu , Yuliang Lin , Meng Sun , Shaoliang Duan , Chao Zhang , Denggao Zhang , Min Liu , Xiaobo Mai , Jiaqi Tan , Zhiwen Wang , Jinggen Liu , Liming Shao , Wei Fu , Yujun Wang , Wei Li","doi":"10.1016/j.ejmech.2026.118591","DOIUrl":"10.1016/j.ejmech.2026.118591","url":null,"abstract":"<div><div>4,5-Epoxymorphinan derivatives represent a privileged chemotype among opioid ligands, with well-established clinical utility, and continue to serve as a widely used scaffold for the development of novel opioid-like therapeutics. This work describes the design and synthesis of a series of <em>N</em>-cyclopropylmethyl-7α-(<em>m</em>-methylaminophenyl)-6,14-<em>endo</em>ethano-northebaine derivatives and identifies compound <strong>8a</strong> as a structurally optimized KOR agonist with high KOR affinity, pronounced MOR/KOR and DOR/KOR subtype selectivity, and marked G-protein bias. <em>In vivo</em>, compound <strong>8a</strong> exhibited robust, dose-dependent antinociceptive activity in both the hot-plate and abdominal constriction assays, with ED<sub>50</sub> values of 8.2 and 0.5 mg/kg, respectively. Nevertheless, the emergence of motor impairment and aversive effects at behaviorally relevant doses underscores a critical limitation of relying solely on cell-based G-protein bias as a predictor of improved central nervous system safety for KOR agonists.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118591"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995782","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}

引用次数: 0

Design and anti-inflammatory activity evaluation of tryptophan analogs as novel dipeptidyl peptidase I inhibitors 新型二肽基肽酶I抑制剂色氨酸类似物的设计及抗炎活性评价

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-19 DOI: 10.1016/j.ejmech.2026.118570

Daxing Shi , Xianan Liu , Jingyuan Huang , Chenxiao Li , Qiansong Chen , Feilong Zhou , Xing Chen

{"title":"Design and anti-inflammatory activity evaluation of tryptophan analogs as novel dipeptidyl peptidase I inhibitors","authors":"Daxing Shi , Xianan Liu , Jingyuan Huang , Chenxiao Li , Qiansong Chen , Feilong Zhou , Xing Chen","doi":"10.1016/j.ejmech.2026.118570","DOIUrl":"10.1016/j.ejmech.2026.118570","url":null,"abstract":"<div><div>Dipeptidyl peptidase I (DPP-I) mediates the processing and maturation of various serine proteases by cleaving dipeptide structures from N-terminus of zymogen proteins. This process enables DPP-I to participate in inflammatory cascades, thereby establishing it as a key therapeutic target for inflammatory diseases. Here, starting from a serendipitously discovered molecular block with weak DPP-I inhibitory activity, a series of tryptophan analogs were designed and synthesized. Following biological activity evaluation, compound <strong>C10b</strong> as a potent DPP-I inhibitor was identified. Through structure-activity relationship and docking analyses, the binding mode and key interactions were elucidated. <em>In vitro</em> results confirmed <strong>C10b</strong> could bind to and inhibit intracellular DPP-I activity, and further down-regulate the activity and expression levels of downstream neutrophil serine proteases, while exhibiting excellent anti-inflammatory activity and regulating the secretion of various inflammatory factors. <em>In vivo</em> results demonstrated <strong>C10b</strong> possessed acceptable toxicity and good pharmacodynamic activity. In the adjuvant-induced arthritis model in rats, <strong>C10b</strong> exerted an anti-inflammatory effect and reversed joint inflammation and tissue damage. Collectively, as a novel DPP-I inhibitor, <strong>C10b</strong> exhibits nice anti-inflammatory activity and considerable potential for further development, which supports its application in development of therapeutic agent for neutrophil-associated inflammatory diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118570"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146001184","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}

引用次数: 0

Epigenetic enzyme inhibitors targeting DNA, histone, and RNA methylation: Mechanisms and therapeutic applications in cancer 靶向DNA、组蛋白和RNA甲基化的表观遗传酶抑制剂：机制及其在癌症中的治疗应用

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-20 DOI: 10.1016/j.ejmech.2026.118590

Yiman Wang , Chen Ma , Xinya Liu , Junkai Cheng , Dan Zhu , Peng Liu , Peng Qi , Xiankai Li , Jian Gu , Qin Wang

{"title":"Epigenetic enzyme inhibitors targeting DNA, histone, and RNA methylation: Mechanisms and therapeutic applications in cancer","authors":"Yiman Wang , Chen Ma , Xinya Liu , Junkai Cheng , Dan Zhu , Peng Liu , Peng Qi , Xiankai Li , Jian Gu , Qin Wang","doi":"10.1016/j.ejmech.2026.118590","DOIUrl":"10.1016/j.ejmech.2026.118590","url":null,"abstract":"<div><div>Epigenetic modifications, such as DNA methylation, histone methylation, and RNA methylation, dynamically regulate gene transcription and play critical roles in cellular differentiation, development, and disease, especially cancer. Inhibitors targeting the enzymes responsible for these modifications have emerged as promising cancer therapies. For instance, DNMT inhibitors (e.g., azacitidine, decitabine) can reactivate tumor suppressor genes via demethylation; HMT inhibitors like tazemetostat and EPZ-5676 modulate chromatin structure to exert anti-tumor effects; and RNA methyltransferase inhibitors such as STM2457 disrupt RNA metabolism to suppress tumor growth. Despite encouraging preclinical and clinical results, challenges including toxicity and drug resistance remain obstacles to broader clinical application. This review summarizes recent advances in epigenetic inhibitor development to support the design of safer and more effective targeted cancer therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118590"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005743","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}

引用次数: 0

Piperazinotriazole-based NK3R antagonists: Rational design, synthesis, and identification of an orally active lead compound 基于哌嗪三唑的NK3R拮抗剂：一种口服活性先导化合物的合理设计、合成和鉴定

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-23 DOI: 10.1016/j.ejmech.2026.118614

Fangxia Zou , Yashi Zhou , Hui Wang , Hengwei Xu , Wenjing Zhang , Yifei Yang , Chunmei Li , Wenyan Wang , Jianzhao Zhang , Hongbo Wang , Liang Ye , Jingwei Tian

{"title":"Piperazinotriazole-based NK3R antagonists: Rational design, synthesis, and identification of an orally active lead compound","authors":"Fangxia Zou , Yashi Zhou , Hui Wang , Hengwei Xu , Wenjing Zhang , Yifei Yang , Chunmei Li , Wenyan Wang , Jianzhao Zhang , Hongbo Wang , Liang Ye , Jingwei Tian","doi":"10.1016/j.ejmech.2026.118614","DOIUrl":"10.1016/j.ejmech.2026.118614","url":null,"abstract":"<div><div>The neurokinin-3 receptor (NK3R) has emerged as a promising non-hormonal therapeutic target for menopausal hot flashes, with fezolinetant being the only clinically approved NK3R antagonist to date. To overcome this therapeutic limitation, we designed a series of imidazolepiperazine derivatives (<strong>17a-17c</strong>, <strong>21</strong>, <strong>23a-23u</strong>), among which <strong>23i(R)</strong> demonstrated superior pharmacological properties including potent NK3R inhibition (IC<sub>50</sub> = 65.42 ± 6.54 nM), strong target binding (IC<sub>50</sub> = 53.61 ± 3.67 nM), excellent membrane permeability (Papp A-B = 27.3 × 10<sup>−6</sup> cm/s; ER = 0.53), and remarkable oral bioavailability (165 %). In ovariectomized rat models, <strong>23i(R)</strong> effectively suppressed luteinizing hormone levels while exhibiting favorable pharmacokinetics and tolerability, establishing it as a promising clinical candidate for further development as a next-generation NK3R antagonist.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118614"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033858","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}

引用次数: 0

Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on phenyl-indole scaffold 基于苯基吲哚支架的新型非甾体维生素D受体激动剂的设计、合成和抗肝纤维化活性

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-20 DOI: 10.1016/j.ejmech.2026.118592

Yu Tong , Nuo Cheng , Chun Guan, Yue Wu, Yi Gao, Shihao Liu, Cong Wang, Can Zhang

{"title":"Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on phenyl-indole scaffold","authors":"Yu Tong , Nuo Cheng , Chun Guan, Yue Wu, Yi Gao, Shihao Liu, Cong Wang, Can Zhang","doi":"10.1016/j.ejmech.2026.118592","DOIUrl":"10.1016/j.ejmech.2026.118592","url":null,"abstract":"<div><div>Hepatic fibrosis, a pathological consequence of chronic liver injury, is characterized by excessive deposition of extracellular matrix (ECM). Activation of hepatic stellate cells (HSCs) is critical to the pathogenesis. Vitamin D receptor (VDR) agonists have been demonstrated to inhibit transforming growth factor-beta 1 (TGF-β1) induced HSC activation, thereby reducing ECM deposition and attenuating the progression of liver fibrosis. Despite their broad therapeutic potential, the clinical translation of VDR agonists has been hampered by the risk of inducing hypercalcemia. To address this limitation, we designed a series of novel non-steroidal VDR agonists based on a phenylindole scaffold and evaluated their anti-fibrotic properties. Among them, compounds <strong>I-7, II-4, II-6</strong>, and <strong>II-8</strong>, exhibited significant inhibition of HSC activation <em>in vitro</em>. Owing to its robust activity, compound <strong>II-8</strong> was selected for further investigation in a bile duct ligation (BDL)-induced liver fibrosis model. Histological analysis confirmed that treatment with <strong>II-8</strong> significantly inhibited the fibrosis progression. Crucially, the hypercalcemia typically associated with VDR agonist therapy was not observed. Hypercalcemia is a major drawback of currently marketed steroidal VDR agonists, which significantly limits their broad clinical application. The compounds we have designed can effectively avoid this hypercalcemia side effect. These findings underscore the potential of <strong>II-8</strong> as a potent therapeutic agent for the treatment of liver fibrosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118592"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014767","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}

引用次数: 0

New fluoxetine analogues as anti-enterovirus agents targeting 2C protein 新的氟西汀类似物作为靶向2C蛋白的抗肠病毒药物

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-28 DOI: 10.1016/j.ejmech.2026.118621

Safeh Khemiri , Marine O. Faucher , Stephane Bourg , Sarah Attoumani-Madi , Carole Yaacoub , Franck Touret , Marc Farag , Mattéo Fermiana Vitorino , Pascal Bonnet , Patrice Vanelle , Samia Aci-Seche , Bruno Coutard , Karine Barral

{"title":"New fluoxetine analogues as anti-enterovirus agents targeting 2C protein","authors":"Safeh Khemiri , Marine O. Faucher , Stephane Bourg , Sarah Attoumani-Madi , Carole Yaacoub , Franck Touret , Marc Farag , Mattéo Fermiana Vitorino , Pascal Bonnet , Patrice Vanelle , Samia Aci-Seche , Bruno Coutard , Karine Barral","doi":"10.1016/j.ejmech.2026.118621","DOIUrl":"10.1016/j.ejmech.2026.118621","url":null,"abstract":"<div><div>There are currently no antiviral drugs available to treat or prevent life-threatening human non-poliovirus enterovirus infections, such as those caused by CV-B3, EV-A71 or EV-D68. Our aim is to develop novel inhibitors that target the non-structural ATPase/Helicase 2C protein, which is involved in the RNA replication process that is essential for enterovirus replication, among other functions. In this study, we describe the optimization of (<em>S</em>)-fluoxetine, a promising hit identified through drug repurposing that binds to an allosteric site on the CV-B3 2C ATPase domain. Our optimization process was guided by rational design, X-ray crystallographic structures, computational docking, and validation by enzyme and cell-based assays, leading to several new inhibitors, among which compound <strong>53</strong> (CV–B3 EC<sub>50</sub> = 0.5 μM and EV-D68 EC<sub>50</sub> = 0.4 μM), a novel anti-enterovirus with higher selectivity indexes than (<em>S</em>)-fluoxetine.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118621"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071902","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}

引用次数: 0

Discovery of benzimidazo-2-amino-1,3,4-thiadiazole carboxylate small-molecule STAT3 inhibitors for colorectal carcinoma therapy 苯并咪唑-2-氨基-1,3,4-噻二唑羧酸盐小分子STAT3抑制剂的发现

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-17 DOI: 10.1016/j.ejmech.2026.118588

Ru Wang , En-Jia Zhou , Chun-Yu Zhang , Liang-Peng Li , Bei-Bei Yang , Ting-Ting Du , Jing Jin , Li Li

{"title":"Discovery of benzimidazo-2-amino-1,3,4-thiadiazole carboxylate small-molecule STAT3 inhibitors for colorectal carcinoma therapy","authors":"Ru Wang , En-Jia Zhou , Chun-Yu Zhang , Liang-Peng Li , Bei-Bei Yang , Ting-Ting Du , Jing Jin , Li Li","doi":"10.1016/j.ejmech.2026.118588","DOIUrl":"10.1016/j.ejmech.2026.118588","url":null,"abstract":"<div><div>To identify potent candidate drugs for colorectal cancer (CRC), a series of <em>N</em>-benzimidazole-1,3,4-thiadiazole-2-amine derivatives featuring diverse ester groups were designed and synthesized, based on our preceding research. Systematic pharmacological evaluation demonstrated their inhibitory effects against the IL-6/JAK/STAT3 signaling pathway and CRC cell lines with constitutively activated STAT3. Among these derivatives, compound <strong>L20</strong> demonstrated the most potent anti-proliferative activity against HCT116 (IC<sub>50</sub> = 0.45 ± 0.05 μM) and other CRC-relevant cell lines. Mechanistic investigations confirmed that <strong>L20</strong> directly binds to STAT3 protein (K<sub>D</sub> = 6.16 μM), specifically interacting with its SH2 domain. This binding resulted in a dose-dependent suppression of STAT3 phosphorylation at Y705 without affecting total STAT3 protein levels. Furthermore, <strong>L20</strong> dose-dependently downregulated both the transcription and expression of cyclin-D1 and c-Myc, two critical downstream effectors of STAT3. Additionally, it induced cell cycle arrest and promoted apoptosis in HCT116 cells in a concentration-dependent manner. Notably, in a murine MC38 subcutaneous xenograft model, <strong>L20</strong> administration (20 mg/kg, i.p.) significantly suppressed tumor growth, achieving a tumor growth inhibition rate of 59.8 %. These results highlight the promise of <strong>L20</strong> as a novel candidate for CRC therapy and establish a compelling basis for the continued develop of STAT3-targeted interventions against CRC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118588"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995781","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}

引用次数: 0

Charting the evolving landscape of kinase hinge-binding chemotypes beyond flatland: a systematic analysis and opportunities for sp3-rich binders 超越平面的激酶铰链结合化学型的演变图景：sp3-Rich结合物的系统分析和机遇

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-19 DOI: 10.1016/j.ejmech.2026.118595

Shangde Liu , Tianlei Han , Zhenyu Zhang , Hui Yu , Albert A. Antolin , Huabin Hu

{"title":"Charting the evolving landscape of kinase hinge-binding chemotypes beyond flatland: a systematic analysis and opportunities for sp3-rich binders","authors":"Shangde Liu , Tianlei Han , Zhenyu Zhang , Hui Yu , Albert A. Antolin , Huabin Hu","doi":"10.1016/j.ejmech.2026.118595","DOIUrl":"10.1016/j.ejmech.2026.118595","url":null,"abstract":"<div><div>ATP-competitive kinase inhibitors represent one of the most successful modalities in targeted therapy, yet their discovery has historically relied on a narrow repertoire of hinge-binding motifs. Here, we report a large-scale structural analysis of 4370 kinase–ligand complexes spanning 289 human protein kinases, providing the most comprehensive publicly available catalogue of hinge-binding scaffolds to date. Systematic extraction and consolidation identified 846 unique hinge binders, enabling quantitative assessment of their frequency, promiscuity, and residue interactions across the kinome. The analysis reveals that hinge binders remain predominantly planar heteroaromatic chemotypes, and that progress over the past three decades has largely involved incremental optimization of these limited motifs rather than exploration of sp<sup>3</sup>-enriched scaffolds. Novel opportunities for chemical innovation were identified through noncanonical interactions, such as halogen bonding, as well as through conformationally restricted designs, including macrocycles to generate sp<sup>3</sup>-enriched hinge-binding moieties. Although limited in number, these examples demonstrate that nonplanar chemotypes can achieve hinge engagement comparable to that of rigid planar binders while substantially expanding the accessible chemical space of kinase inhibitors. Collectively, this work delineates the structural landscape of kinase hinge binders and provides a hinge-binding resource to enable scaffold hopping and focused library design, while identifying opportunities for the discovery of next-generation ATP-competitive kinase inhibitors within a highly competitive therapeutic space.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118595"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146001183","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}

引用次数: 0

Research progress of curcumin and its derivatives as anti-inflammatory agents: From molecular mechanism to clinical application 姜黄素及其衍生物抗炎药物的研究进展：从分子机制到临床应用

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-14 DOI: 10.1016/j.ejmech.2026.118584

Nan Wu , Yue Zhang , Chengyu Cui , Chonghao Sun, Zhixian Cui, Hui Li, Junyi Jin, Mingjing Zhao, Xiongjie Yin, Lili Jin, Changhao Zhang

{"title":"Research progress of curcumin and its derivatives as anti-inflammatory agents: From molecular mechanism to clinical application","authors":"Nan Wu , Yue Zhang , Chengyu Cui , Chonghao Sun, Zhixian Cui, Hui Li, Junyi Jin, Mingjing Zhao, Xiongjie Yin, Lili Jin, Changhao Zhang","doi":"10.1016/j.ejmech.2026.118584","DOIUrl":"10.1016/j.ejmech.2026.118584","url":null,"abstract":"<div><div>Curcumin, a diarylheptane compound, which has multidimensional pharmacological activities such as anti-inflammatory, anti-oxidant, anti-tumor, and neuroprotective effects. However, its poor water solubility, low bioavailability, and metabolic instability seriously hinder its clinical application. This article provides a systematic review of the research progress of CUR: elaborating on the chemical structural characteristics of CUR and its structure-activity relationship with activity. Based on chemical structural characteristics, the molecular mechanism of its anti-inflammatory pharmacological effects is analyzed by targeting multiple signaling pathways, revealing its “multi-target, multi pathway” mode of action. Focusing on the bottleneck of bioavailability, this article summarizes the innovative design of structural modification strategies and novel delivery systems, demonstrating their potential to break through pharmacokinetic limitations by enhancing solubility, avoiding first pass effects, and achieving targeted delivery. Further combining clinical applications, summarize the current status of CUR in the treatment of inflammation related diseases. This review explores possible ways to promote the transformation of CUR from a “dietary supplement” to a “precision medicine” based on future development prospects, providing theoretical support for the in-depth development of natural products.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118584"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968472","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}

引用次数: 0