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

Halogen-methyl hybridization unlocks orally bioavailable STING agonist for tumor immunotherapy 卤素-甲基杂交为肿瘤免疫治疗提供口服生物可利用的STING激动剂

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-03-15 Epub Date: 2026-01-22 DOI: 10.1016/j.ejmech.2026.118594

Guo-Feng Xin , Qiang-Sheng Zhu , Nan-Nan Chen , Lin-Lin Li , Ye-Ling Zhou , Si-Shuo Liu , Si-Jia Gong , Bei-Duo Wu , Yin-Quan Huang , Qi-Dong You , Xiao-Li Xu

The activation of the stimulator of interferon genes (STING) represents a pivotal strategy in tumor immunotherapy. Currently, there is a pressing need for more small-molecule STING agonists to advance into clinical trials. In this study, we developed a series of benzofuran derivatives as novel non-nucleotide STING agonists through structure-based drug design strategies. Systematic optimization yielded the candidate compound X41, which exhibits potent STING agonist activity and favorable drug-like properties. Structural refinement was achieved through R³-position ''chloro'' (Cl) and R¹-position ''methyl effect'' (CH₃) substituents, optimizing the balance between target potency and membrane permeability. Mechanistic characterization revealed that X41 demonstrates dose-dependent activation of the STING signaling pathway in THP1-Dual cells, significantly inducing downstream IFN-β and CXCL10 expression. In the MC38 syngeneic tumor model, oral administration of X41 (50 mg/kg) achieved substantial tumor growth inhibition (TGI = 88.04 %), while intraperitoneal dosing (20 mg/kg) induced complete tumor regression in 50 % of the treated mice. Pharmacokinetic profiling demonstrated favorable plasma exposure and metabolic stability, with an oral half-life (T_1/2) of 9.92 h. These integrated preclinical studies establish X41 as a structurally novel oral STING agonist with significant translational potential, positioning it as a promising candidate for the immunotherapy of solid tumors.

干扰素刺激因子基因（STING）的激活是肿瘤免疫治疗的关键策略。目前，迫切需要更多的小分子STING激动剂进入临床试验。在这项研究中，我们通过基于结构的药物设计策略开发了一系列苯并呋喃衍生物作为新型非核苷酸STING激动剂。系统优化得到候选化合物X41，它具有强大的STING激动剂活性和良好的药物样特性。通过r3位置的“氯”（Cl）和r1位置的“甲基效应”（CH3）取代基实现结构优化，优化了靶效和膜透性之间的平衡。机制表征显示，X41在THP1-Dual细胞中表现出剂量依赖性的STING信号通路激活，显著诱导下游IFN-β和CXCL10的表达。在MC38同基因肿瘤模型中，口服X41 （50 mg/kg）可显著抑制肿瘤生长（TGI = 88.04%），而腹腔注射X41 （20 mg/kg）可使50%的小鼠肿瘤完全消退。药代动力学分析显示良好的血浆暴露和代谢稳定性，口服半衰期（T1/2）为9.92小时。这些综合临床前研究证实X41是一种结构新颖的口服STING激动剂，具有显著的翻译潜力，将其定位为实体肿瘤免疫治疗的有希望的候选者。

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引用次数: 0

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 Q1 CHEMISTRY, MEDICINAL

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

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.

尽管PROTAC技术通过降解以前不可药物的蛋白质而彻底改变了药物发现，但传统PROTACs的临床翻译受到E3连接酶可用性的限制、次优的药物样性质和狭窄的靶标范围的阻碍。近年来，多种新型PROTAC设计策略的出现，如伴侣介导的PROTAC （CHAMP）、mini-PROTAC、共价PROTAC、HyTTD、pro-PROTAC等，将该技术提升到新的高度，加速了其临床进展。然而，一个关键的问题仍然存在：我们如何在这些选项中选择最合适的策略？我们总结并分析了它们的优势和局限性，包括E3连接酶依赖性和E3连接酶非依赖性降解物策略的优化和扩展、不可药物靶标降解物策略、连接物优化和扩展策略以及pro-PROTAC策略。此外，我们还提供了基于特定目标特征选择合适策略的指导，以设计有效的PROTAC，旨在促进这些创新方法向临床应用的转化。

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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 Q1 CHEMISTRY, MEDICINAL

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

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 N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives and identifies compound 8a as a structurally optimized KOR agonist with high KOR affinity, pronounced MOR/KOR and DOR/KOR subtype selectivity, and marked G-protein bias. In vivo, compound 8a exhibited robust, dose-dependent antinociceptive activity in both the hot-plate and abdominal constriction assays, with ED₅₀ 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.

4,5-环氧morphinan衍生物在阿片类配体中是一种特殊的化学型，具有良好的临床应用，并继续作为一种广泛使用的支架，用于开发新型阿片类药物。本研究设计和合成了一系列n -环丙基甲基-7α-（m-甲基氨基苯基）-6,14-内乙醇-北啡衍生物，并鉴定出化合物8a是一种结构优化的KOR激动剂，具有高KOR亲和力，明显的MOR/KOR和DOR/KOR亚型选择性，以及明显的g蛋白偏倚。在体内，化合物8a在热板和腹部收缩实验中均表现出强大的剂量依赖性抗伤感受活性，ED50值分别为8.2和0.5 mg/kg。然而，在行为相关剂量下出现的运动损伤和不良反应强调了仅依赖基于细胞的g蛋白偏差作为改善KOR激动剂中枢神经系统安全性的预测指标的关键局限性。

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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 Q1 CHEMISTRY, MEDICINAL

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

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 C10b as a potent DPP-I inhibitor was identified. Through structure-activity relationship and docking analyses, the binding mode and key interactions were elucidated. In vitro results confirmed C10b 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. In vivo results demonstrated C10b possessed acceptable toxicity and good pharmacodynamic activity. In the adjuvant-induced arthritis model in rats, C10b exerted an anti-inflammatory effect and reversed joint inflammation and tissue damage. Collectively, as a novel DPP-I inhibitor, C10b 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.

二肽基肽酶I （DPP-I）通过从酶原蛋白的n端切割二肽结构来介导各种丝氨酸蛋白酶的加工和成熟。这一过程使dpp - 1参与炎症级联反应，从而使其成为炎症性疾病的关键治疗靶点。在这里，从偶然发现的具有弱dpp - 1抑制活性的分子块开始，设计并合成了一系列色氨酸类似物。经生物活性评价，化合物C10b是一种有效的dpp - 1抑制剂。通过构效关系和对接分析，阐明了它们的结合模式和关键相互作用。体外实验结果证实C10b能结合并抑制胞内dpp - 1活性，进一步下调下游中性粒细胞丝氨酸蛋白酶的活性和表达水平，同时表现出优异的抗炎活性，调节多种炎症因子的分泌。体内实验结果表明，C10b具有良好的毒性和药效学活性。在佐剂诱导的大鼠关节炎模型中，C10b具有抗炎作用，可逆转关节炎症和组织损伤。综上所述，C10b作为一种新型的DPP-I抑制剂，具有良好的抗炎活性和巨大的开发潜力，支持其在中性粒细胞相关炎症性疾病治疗剂开发中的应用。

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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 Q1 CHEMISTRY, MEDICINAL

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

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.

表观遗传修饰，如DNA甲基化、组蛋白甲基化和RNA甲基化，动态调节基因转录，并在细胞分化、发育和疾病，特别是癌症中发挥关键作用。针对负责这些修饰的酶的抑制剂已经成为有希望的癌症治疗方法。例如，DNMT抑制剂（如阿扎胞苷、地西他滨）可以通过去甲基化重新激活肿瘤抑制基因；他zemetostat和EPZ-5676等HMT抑制剂通过调节染色质结构发挥抗肿瘤作用；RNA甲基转移酶抑制剂如STM2457破坏RNA代谢抑制肿瘤生长。尽管临床前和临床结果令人鼓舞，但包括毒性和耐药性在内的挑战仍然是广泛临床应用的障碍。本文综述了表观遗传抑制剂的最新进展，以支持设计更安全、更有效的靶向癌症治疗方法。

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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 Q1 CHEMISTRY, MEDICINAL

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

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 I-7, II-4, II-6, and II-8, exhibited significant inhibition of HSC activation in vitro. Owing to its robust activity, compound II-8 was selected for further investigation in a bile duct ligation (BDL)-induced liver fibrosis model. Histological analysis confirmed that treatment with II-8 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 II-8 as a potent therapeutic agent for the treatment of liver fibrosis.

肝纤维化是慢性肝损伤的病理结果，其特征是细胞外基质（ECM）过度沉积。肝星状细胞（hsc）的激活是其发病机制的关键。维生素D受体（VDR）激动剂已被证明可以抑制转化生长因子-β1 （TGF-β1）诱导的HSC活化，从而减少ECM沉积，减缓肝纤维化的进展。尽管具有广泛的治疗潜力，但VDR激动剂的临床翻译一直受到诱导高钙血症的风险的阻碍。为了解决这一限制，我们设计了一系列基于苯吲哚支架的新型非甾体VDR激动剂，并评估了它们的抗纤维化性能。其中化合物I-7、II-4、II-6和II-8在体外对HSC活化有明显的抑制作用。由于其强大的活性，化合物II-8被选择在胆管结扎（BDL）诱导的肝纤维化模型中进行进一步研究。组织学分析证实，II-8治疗可显著抑制纤维化进展。关键是，没有观察到与VDR激动剂治疗典型相关的高钙血症。高钙血症是目前上市的甾体VDR激动剂的一个主要缺点，这极大地限制了它们的广泛临床应用。我们设计的化合物可以有效地避免这种高钙血症的副作用。这些发现强调了II-8作为治疗肝纤维化的有效药物的潜力。

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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 Q1 CHEMISTRY, MEDICINAL

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

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 (17a-17c, 21, 23a-23u), among which 23i(R) demonstrated superior pharmacological properties including potent NK3R inhibition (IC₅₀ = 65.42 ± 6.54 nM), strong target binding (IC₅₀ = 53.61 ± 3.67 nM), excellent membrane permeability (Papp A-B = 27.3 × 10⁻⁶ cm/s; ER = 0.53), and remarkable oral bioavailability (165 %). In ovariectomized rat models, 23i(R) 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.

神经激肽-3受体（NK3R）已成为一种有前景的绝经期潮热的非激素治疗靶点，非唑啉奈坦是迄今为止唯一临床批准的NK3R拮抗剂。为了克服这个治疗局限性,我们设计了一系列imidazolepiperazine衍生品(17 a-17c, 21日23 a-23u),其中23我(R)演示了优越的药理特性包括强有力的NK3R抑制(IC50 = 65.42 ±6.54  海里),强大的目标绑定(IC50 = 53.61 ±3.67  海里),优秀的膜透性(Papp a - b = 27.3 × 10−6 cm / s; ER = 0.53),和非凡的口服生物利用度(165 %)。在去卵巢大鼠模型中，23i(R)有效抑制黄体生成素水平，同时表现出良好的药代动力学和耐受性，这使其成为下一代NK3R拮抗剂的临床候选药物。

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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 Q1 CHEMISTRY, MEDICINAL

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

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 (S)-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 53 (CV–B3 EC₅₀ = 0.5 μM and EV-D68 EC₅₀ = 0.4 μM), a novel anti-enterovirus with higher selectivity indexes than (S)-fluoxetine.

目前没有抗病毒药物可用于治疗或预防危及生命的人类非脊髓灰质炎病毒肠道病毒感染，例如由CV-B3、EV-A71或EV-D68引起的感染。我们的目标是开发针对非结构性atp酶/解旋酶2C蛋白的新型抑制剂，该蛋白参与肠道病毒复制所必需的RNA复制过程，以及其他功能。在这项研究中，我们描述了(S)-氟西汀的优化，这是一种通过药物重组发现的有前途的药物，可以结合CV-B3 2C atp酶结构域的变构位点。我们的优化过程以合理设计、x射线晶体结构、计算对接以及基于酶和细胞的实验验证为指导，得到了几种新的肠道病毒抑制剂，其中化合物53 （CV-B3 EC50 = 0.5 μM和EV-D68 EC50 = 0.4 μM）是一种比(S)-氟西汀具有更高选择性指标的新型肠道病毒抑制剂。

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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 Q1 CHEMISTRY, MEDICINAL

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

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.

姜黄素是一种二芳基庚烷化合物，具有抗炎、抗氧化、抗肿瘤、神经保护等多方面药理作用。但其水溶性差、生物利用度低、代谢不稳定等问题严重阻碍了其临床应用。本文系统综述了CUR的研究进展，阐述了CUR的化学结构特点及其构效关系。根据其化学结构特点，通过靶向多种信号通路，分析其抗炎药理作用的分子机制，揭示其“多靶点、多途径”的作用模式。针对生物利用度的瓶颈，本文综述了结构修饰策略和新型给药系统的创新设计，展示了它们通过提高溶解度、避免首过效应和实现靶向给药来突破药代动力学限制的潜力。进一步结合临床应用，总结CUR在炎症相关疾病治疗中的现状。本文结合未来发展前景，探讨推动CUR从“膳食补充剂”向“精准医疗”转变的可能途径，为天然产物的深入开发提供理论支持。

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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 Q1 CHEMISTRY, MEDICINAL

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

To identify potent candidate drugs for colorectal cancer (CRC), a series of N-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 L20 demonstrated the most potent anti-proliferative activity against HCT116 (IC₅₀ = 0.45 ± 0.05 μM) and other CRC-relevant cell lines. Mechanistic investigations confirmed that L20 directly binds to STAT3 protein (K_D = 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, L20 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, L20 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 L20 as a novel candidate for CRC therapy and establish a compelling basis for the continued develop of STAT3-targeted interventions against CRC.

为了寻找结直肠癌（CRC）的有效候选药物，我们在前期研究的基础上设计并合成了一系列具有不同酯基的n -苯并咪唑-1,3,4-噻二唑-2-胺衍生物。系统药理学评价表明，它们对IL-6/JAK/STAT3信号通路和组成性激活STAT3的CRC细胞系具有抑制作用。在这些衍生物中，化合物L20对HCT116和其他crc相关细胞株的抑制活性最强（IC50 = 0.45±0.05 μM）。机制研究证实L20直接结合STAT3蛋白（KD = 6.16 μM），特异性地与STAT3蛋白的SH2结构域相互作用。这种结合导致了Y705位点STAT3磷酸化的剂量依赖性抑制，而不影响STAT3总蛋白水平。此外，L20剂量依赖性地下调了STAT3的两个关键下游效应因子cyclin-D1和c-Myc的转录和表达。此外，它还以浓度依赖性的方式诱导HCT116细胞周期阻滞和促进细胞凋亡。值得注意的是，在小鼠MC38皮下异种移植模型中，L20给药（20 mg/kg, i.p）显著抑制肿瘤生长，肿瘤生长抑制率达到59.8%。这些结果突出了L20作为结直肠癌治疗的新候选药物的前景，并为继续开发以stat3为目标的结直肠癌干预措施奠定了强有力的基础。

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引用次数: 0