European Journal of Medicinal Chemistry最新文献_第6页

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 : 2026-01-17 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

Small-molecule fluorescent probes for the aminergic GPCRs – What new tool compounds do we have post-2014 and what can they do? 用于胺类gpcr的小分子荧光探针——2014年后我们有哪些新的工具化合物？它们能做什么？

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-16 DOI: 10.1016/j.ejmech.2026.118579

Christopher Zi Qian Choo, Joey Yun Xuan Ching, Myra Mazhar Ud Deen, Zhi Yuan Kok

Aminergic G protein-coupled receptors (GPCRs) are heavily involved in the physiological functions of the human body and represent prominent drug targets for numerous diseases. Despite extensive work over the years, knowledge gaps persist as not all aminergic GPCRs are currently drugged. This gap could be addressed by using small-molecule fluorescent probes across a range of assay formats and experiments to obtain deeper insights into the molecular pharmacology of these receptors. This review highlights key developments from 2014 to 2024 in the design and application of fluorescent probes targeting aminergic GPCRs, featuring a total of 36 fluorescent probes spanning all prominent aminergic GPCR subfamilies: adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. This review provides a detailed overview of the approaches to probe design, their pharmacological profiles and their reported utilities in ligand binding assays and imaging studies. In recent years, these applications have expanded to include ex vivo and in vivo studies in both mice and human tissue models. With the integration of cutting-edge image processing and artificial intelligence-driven image recognition technologies, fluorescent probes will remain indispensable tools for investigating the molecular pharmacology of aminergic GPCRs, playing a crucial role in driving forward drug discovery in this field.

氨基G蛋白偶联受体（gpcr）广泛参与人体的生理功能，是许多疾病的重要药物靶点。尽管多年来进行了广泛的工作，但知识差距仍然存在，因为目前并非所有胺能gpcr都被药物治疗。这一差距可以通过在一系列分析格式和实验中使用小分子荧光探针来解决，以更深入地了解这些受体的分子药理学。本文综述了2014年至2024年针对胺能GPCR的荧光探针的设计和应用的主要进展，包括36个荧光探针，涵盖了所有主要的胺能GPCR亚家族：肾上腺素能、多巴胺能、组胺能、毒菌碱和血清素能受体。这篇综述提供了探针设计方法的详细概述，它们的药理学特征和它们在配体结合分析和成像研究中的应用。近年来，这些应用已经扩展到包括小鼠和人体组织模型的离体和体内研究。随着先进的图像处理和人工智能驱动的图像识别技术的融合，荧光探针将继续成为研究氨基gpcr分子药理学不可或缺的工具，在推动该领域的药物发现方面发挥着至关重要的作用。

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引用次数: 0

Discover of a highly effective covalent inhibitor of CDK6 for triple-negative breast cancer treatment 发现一种用于三阴性乳腺癌治疗的高效共价CDK6抑制剂

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-15 DOI: 10.1016/j.ejmech.2026.118565

Jingting Zeng , Fucheng Yin , Yongwei Fan , Keying Zheng , Zifeng Zhang , Liu Liu , Renxin Jiang , Na Li , Fanglan Liu , Chunhua Xia , Cheng Wang

CDK4/6 inhibitors are effective in treating HR+/HER2− breast cancer, but they have limitations in treating TNBC and drug-resistant breast cancer. To overcome this challenge, we designed and synthesized a series of novel covalent inhibitors for CDK6 that contain the Palbociclib core pharmacophore. The most promising compound, C32, showed good inhibitory activity against CDK6 (IC₅₀ = 0.013 μM) and good inhibitory effects on MDA-MB-231 (IC₅₀ = 0.061 μM), MDA-MB-468 (IC₅₀ = 0.080 μM) and BT-549 (IC₅₀ = 0.044 μM) cells. Compared with that of Palbociclib, the growth inhibitory activities against these two cell types increased by approximately 200-fold. Compound C32 can effectively inhibit the proliferation and migration of TNBC cells and induce apoptosis and S-phase cell cycle arrest. C32 can also induce excessive mitochondrial oxidative phosphorylation by remodeling cellular metabolic patterns, leading to the generation of ROS and mitochondrial damage. In vivo experiments further demonstrated that C32 has a favorable safety profile and pharmacokinetic properties, while exhibiting significant anti-TNBC effects. As a novel CDK6 covalent inhibitor, C32 is expected to be a candidate compound for the treatment of TNBC.

CDK4/6抑制剂治疗HR+/HER2-乳腺癌有效，但在治疗TNBC和耐药乳腺癌方面存在局限性。为了克服这一挑战，我们设计并合成了一系列含有Palbociclib核心药效团的新型CDK6共价抑制剂。其中，最有希望的化合物C32对CDK6具有良好的抑制活性（IC50 = 0.013 μM），对MDA-MB-231 （IC50 = 0.061 μM）、MDA-MB-468 （IC50 = 0.080 μM）和BT-549 （IC50 = 0.044 μM）细胞具有良好的抑制作用。与帕博西尼相比，对这两种细胞类型的生长抑制活性提高了约200倍。化合物C32能有效抑制TNBC细胞的增殖和迁移，诱导细胞凋亡和s期细胞周期阻滞。C32还可以通过重塑细胞代谢模式诱导线粒体过度氧化磷酸化，导致ROS的产生和线粒体损伤。体内实验进一步证明C32具有良好的安全性和药代动力学特性，同时具有显著的抗tnbc作用。作为一种新型CDK6共价抑制剂，C32有望成为治疗TNBC的候选化合物。

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引用次数: 0

Discovery of potent and orally bioavailable benzothiazole-benzenesulfonamide derivatives as ABCA1 upregulators for the management of dyslipidemia 发现有效的口服苯并噻唑-苯磺酰胺衍生物作为ABCA1上调剂用于管理血脂异常

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-15 DOI: 10.1016/j.ejmech.2026.118582

Wenyan Li , Lijuan Lei , Guosheng Zhang , Yunjin Zhang , Yujie Wang , Yexiang Wu , Ren Sheng , Guijun Yang , Yanni Xu , Hongtao Liu

ATP-binding cassette transporter A1 (ABCA1), a key regulator of cholesterol efflux and reverse cholesterol transport, represents a promising therapeutic target for atherosclerosis. However, small-molecule ABCA1 upregulators combining high potency and drug-like properties remain scarce. Through rational structure optimization, we designed and synthesized a series of novel benzothiazole-benzenesulfonamide derivatives. These compounds were systematically evaluated by ABCA1 upregulating activity test, followed by mRNA and protein expression analysis of ABCA1, murine macrophages cholesterol efflux experiments, safety assessment, and in vivo efficacy studies in hyperlipidemic golden hamsters and pharmacokinetic (PK) profiling in ICR mice. Several derivatives, particularly compound 85 demonstrated unprecedented ABCA1 upregulating activity (up to 578 %, EC₅₀ = 0.15 μM). Compounds 25, 56, 68, 85 and 87 significantly induced ABCA1 expression at both mRNA and protein levels, promoted cholesterol efflux in RAW264.7 macrophage cells, and exhibited favorable safety profiles in acute toxicity tests. In hyperlipidemic golden hamsters, these compounds markedly improved plasma lipid profiles—notably increasing HDL-C levels by up to 44 % while effectively reducing TC and TG. Importantly, 85 and 87 displayed exceptional PK properties with oral bioavailability >90 % and systemic exposure significantly superior to conventional lipid-lowering drugs.

atp结合盒转运蛋白A1 （ABCA1）是胆固醇外排和逆向胆固醇转运的关键调节因子，是动脉粥样硬化的一个有希望的治疗靶点。然而，结合高效力和药物样特性的小分子ABCA1上调剂仍然稀缺。通过合理的结构优化，设计合成了一系列新型苯并噻唑-苯磺酰胺衍生物。通过ABCA1上调活性试验、ABCA1 mRNA和蛋白表达分析、小鼠巨噬细胞胆固醇外排实验、安全性评估、高脂血症金仓鼠体内药效研究和ICR小鼠药代动力学（PK）分析，对这些化合物进行系统评价。一些衍生物，特别是化合物85，显示出前所未有的ABCA1上调活性（高达578%，EC50 = 0.15 μM）。化合物25、56、68、85和87可显著诱导ABCA1 mRNA和蛋白水平的表达，促进RAW264.7巨噬细胞中的胆固醇外排，并在急性毒性试验中表现出良好的安全性。在高脂血症的金仓鼠中，这些化合物显著改善了血浆脂质谱——显著提高HDL-C水平达44%，同时有效降低TC和TG。重要的是，85和87表现出特殊的PK特性，口服生物利用度>； 90%，全身暴露明显优于传统的降脂药物。

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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 : 2026-01-14 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

Broadening the horizon: The promise of PROTACs in non-malignant disorders 拓宽视野：PROTACs在非恶性疾病中的前景

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-14 DOI: 10.1016/j.ejmech.2026.118586

Liping Fu , Gongruixue Zeng , Yu Cao , Yueli He , Yaping Zhao , Chongmei Tian , Jinbai Chen , Hualin Feng , Jianjun Xi , Jingsong Shao , Jianhua Tao

Proteolysis-targeting chimeras (PROTACs) are an innovative therapeutic modality that harnesses the ubiquitin-proteasome system (UPS) to degrade target proteins, offering a promising strategy against conventionally “undruggable” proteins. While substantial progress has been made in cancer therapy, this review focuses on recent advances in PROTAC applications to non-oncological diseases, including immune, metabolic, neurodegenerative, and infectious disorders. We systematically evaluate the therapeutic potential and clinical prospects of PROTACs in these areas, aiming to provide new perspectives for expanding the therapeutic landscape of this technology.

蛋白水解靶向嵌合体（PROTACs）是一种利用泛素-蛋白酶体系统（UPS）降解靶蛋白的创新治疗方式，为对抗传统的“不可药物”蛋白提供了一种有前途的策略。虽然PROTAC在癌症治疗方面取得了实质性进展，但本文主要介绍PROTAC在非肿瘤疾病（包括免疫、代谢、神经退行性和感染性疾病）中的应用进展。我们系统地评价了PROTACs在这些领域的治疗潜力和临床前景，旨在为扩大该技术的治疗前景提供新的视角。

引用次数: 0

Autophagy-tethering compounds (ATTECs) as an emerging and potentially transformative drug discovery approach 自噬系固化合物（attec）是一种新兴的、具有潜在变革性的药物发现方法

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-14 DOI: 10.1016/j.ejmech.2026.118585

Zhi Ying Dorothy Wong , Xinyi Kang , Yaoyao Shi , Rui Fan , Chenchen Zhang , Delin Min , Nannan Sun , Youzhen Ma , Mei-Lin Tang

Targeted protein degradation (TPD) strategies leveraging the ubiquitin-proteasome system (UPS), such as proteolysis-targeting chimeras (PROTACs), have gained wide recognition. While the UPS predominantly degrades short-lived soluble proteins, the lysosome-mediated system (LMS) excels at processing larger substrates, including protein aggregates, organelles, and macromolecular complexes. Recently, autophagy-tethering compounds (ATTECs) have emerged as a promising strategy for targeted degradation, harnessing the autophagy-lysosome system (ALS) to enable proximity-induced degradation. These heterobifunctional molecules, composed of LC3-binding warheads and TOI (target of interest) ligands linked together, provide therapeutic potential against disease-causing targets. This review outlines the therapeutic applications of ATTECs in human diseases, highlights recent progress in their development, and explores future opportunities for expanding this emerging class of degradation technologies through ALS from medicinal chemistry perspective.

利用泛素-蛋白酶体系统（UPS）的靶向蛋白降解（TPD）策略，如靶向蛋白水解嵌合体（PROTACs），已经得到了广泛的认可。虽然UPS主要降解短寿命可溶性蛋白质，但溶酶体介导系统（LMS）擅长处理较大的底物，包括蛋白质聚集体、细胞器和大分子复合物。最近，自噬系固化合物（attec）已经成为一种有前途的靶向降解策略，利用自噬溶酶体系统（ALS）来实现邻近诱导的降解。这些异双功能分子由lc3结合弹头和TOI（感兴趣的靶标）配体连接在一起组成，提供了针对致病靶标的治疗潜力。本文概述了attec在人类疾病中的治疗应用，重点介绍了其发展的最新进展，并从药物化学的角度探讨了通过ALS扩展这类新兴降解技术的未来机会。

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引用次数: 0

Small-molecule modulators of the androgen receptor N-terminal domain: Advances in medicinal chemistry for prostate cancer 雄激素受体n端结构域的小分子调节剂：前列腺癌药物化学研究进展

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-13 DOI: 10.1016/j.ejmech.2026.118580

Inderpal Sekhon, Dennis Ashong, Guanglin Chen, Qiao-Hong Chen

Resistance to androgen receptor (AR) therapies in prostate cancer frequently arises from ligand-binding domain (LBD) mutations or the expression of LBD-truncated splice variants such as AR-V7. As these variants retain a functional N-terminal domain (NTD) essential for transcriptional activity, the intrinsically disordered NTD has become an attractive therapeutic target. This review integrates recent advances in targeting the AR NTD, emphasizing both classical antagonists and emerging mechanistic strategies. The pioneering EPI compounds established proof of concept for small-molecule inhibition of the AR NTD, with two analogues progressing to clinical trials. Subsequent discovery efforts have yielded structurally diverse NTD antagonists from natural products and synthetic libraries. Mechanism-focused approaches have garnered increasing interest; small molecules such as UT-143 and ET-516 disrupt AR-driven condensates formed via liquid-liquid phase separation, impairing oncogenic transcription. To complement these approaches, other innovative modalities are also being developed, including bispecific antibodies delivering intracellular anti-NTD fragments, NTD-targeting degraders (e.g., PROTACs), and urea-based antagonists selective for AR splice variants. Disrupting critical protein-protein interactions, such as those between the AR NTD and coactivators, offers an additional strategy to suppress AR activity. Advances in screening platforms and the optimization of structure-activity relationships are beginning to address the challenges of targeting disordered protein domains. With agents like EPI-7386 entering clinical evaluation and others advancing through preclinical development, AR NTD-targeted therapies represent a promising avenue to overcome resistance in castration-resistant prostate cancer (CRPC), potentially in combination with existing LBD-directed treatments to achieve more durable disease control.

前列腺癌对雄激素受体（AR）治疗的耐药性通常是由配体结合结构域（LBD）突变或LBD截断剪接变体（如AR- v7）的表达引起的。由于这些变异保留了对转录活性至关重要的功能性n端结构域（NTD），因此内在紊乱的NTD已成为一个有吸引力的治疗靶点。本文综述了针对AR NTD的最新进展，强调了经典拮抗剂和新兴的机制策略。开创性的EPI化合物建立了小分子抑制AR NTD的概念证明，其中两种类似物正在进行临床试验。随后的发现工作已经从天然产物和合成文库中获得了结构多样的NTD拮抗剂。以机制为重点的方法引起了越来越多的兴趣；UT-143和ET-516等小分子破坏液-液相分离形成的ar驱动凝聚物，损害致癌转录。为了补充这些方法，其他创新模式也在开发中，包括递送细胞内抗ntd片段的双特异性抗体、靶向ntd的降解物（如PROTACs）和选择性AR剪接变体的尿素拮抗剂。破坏关键的蛋白质-蛋白质相互作用，如AR NTD和共激活因子之间的相互作用，提供了抑制AR活性的另一种策略。筛选平台的进步和结构-活性关系的优化开始解决靶向无序蛋白质结构域的挑战。随着EPI-7386等药物进入临床评估和其他药物的临床前开发，AR - ntd靶向治疗代表了克服去势抵抗性前列腺癌（CRPC）耐药的有希望的途径，可能与现有的lbd靶向治疗相结合，以实现更持久的疾病控制。

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引用次数: 0

Current landscape and therapeutic prospects of indole hybrids for prostate cancer treatment: A mini-review 吲哚复合物治疗前列腺癌的现状和治疗前景：综述

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-13 DOI: 10.1016/j.ejmech.2026.118583

Zhi Xu, Yang Shi, Bowen Pan, Huabin Wang

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 via 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.

在男性所有癌症类型中，前列腺癌的发病率排名第二，死亡率排名第五。这一引人注目的流行病学概况凸显了其作为对全球男性生命和健康构成严重威胁的主要健康问题的地位。尽管前列腺癌的传统化疗和靶向治疗已经取得了相当大的进展，但仍然存在一些关键的挑战，包括高转移性、获得性耐药和晚期患者的不良预后，这突出了开发新的治疗策略的必要性。吲哚杂合体是一种多功能且有前景的抗癌支架，通过将吲哚部分与其他药物载体整合而成，在前列腺癌治疗中表现出突出的多靶点调节能力，能够同时调节关键的致癌途径，以解决激素敏感亚型和去势抵抗亚型的复杂分子机制。与单支架衍生物相比，吲哚杂合体通过缀合部分之间的协同作用显示出增强的抗癌效力和降低的脱靶毒性，同时也显示出克服耐药性的潜力，通过绕过单靶点突变诱导的耐药性和抑制ABC转运蛋白来逆转多药耐药性。此外，它们的结构灵活性有助于结构优化，以改善药代动力学特性和针对特定前列腺癌表型的定制疗效，使吲哚杂合物成为开发新型治疗药物的有价值的候选者，以满足前列腺癌治疗中未满足的临床需求。本文综述了2021年至今具有抗前列腺癌活性的吲哚杂合体的最新研究进展，力求为开发新的前列腺癌治疗药物开辟新的方向。

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引用次数: 0

Rational design of an NLRP3 inhibitor with superior efficacy and safety for gout therapy 一种具有优越疗效和安全性的NLRP3抑制剂用于痛风治疗的合理设计

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-13 DOI: 10.1016/j.ejmech.2026.118578

Yichao Kong , Mengjun Su , Caihong Jiang , Haonan Feng , Yingjie Hu , Donglai Li , Zhenyu Mao , Fengling Liu , Fuli Zhu , Yue Guo , Shuhua Ren , Man Chi , Ting Qiu , Yaxia Yuan , Weiwei Huang , Lei Ma , Xiabin Chen

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 M48, 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, M48 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, M48'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.

痛风是由尿酸盐晶体诱导的炎症引起的，由于目前治疗的疗效和毒性有限，痛风仍然是一个治疗挑战。靶向NLRP3炎性小体是痛风发病机制的核心驱动因素，提供了一个有希望的策略。虽然MCC950是一种有效的NLRP3抑制剂，显示出临床潜力，但由于肝毒性而停药，表明迫切需要更安全的替代品。在这里，我们通过合理的药物设计方法来开发下一代NLRP3抑制剂来解决这些挑战。通过利用低温电镜结构和分子动力学（MD）模拟MCC950-NLRP3复合物，我们确定了呋喃部分附近的结构动态区域和相邻的未占用的疏水口袋。针对该口袋的系统结构优化使M48的设计成为可能，该衍生物具有优越的抗炎活性（IC50 = 11.9 nM），良好的口服生物利用度（大鼠89.7%），并且与MCC950相比具有更高的安全性。在msu诱导的小鼠痛风模型中，与吲哚美辛相比，M48表现出更好的抗炎和镇痛作用，其疗效与秋水仙碱相当。该设计策略基于对配体-蛋白质相互作用的计算见解，展示了优化小分子抑制剂的科学严谨性和广泛适用性。值得注意的是，M48的增强疗效和降低的肝毒性风险验证了该方法在解决痛风和其他nlrp3相关疾病未满足的临床需求方面的潜力。

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引用次数: 0