European Journal of Medicinal Chemistry最新文献

{"title":"Discovery and structure-activity relationship studies of 3-pyridazinesulfonyl derivatives as a new class of inhibitors against NLRP3 inflammasome-dependent pyroptosis","authors":"Jinshan Nan ,&nbsp;Shanmian Ji ,&nbsp;Nenghua Zhou ,&nbsp;Yan Jiao ,&nbsp;Yun Zhang ,&nbsp;Shengyong Yang ,&nbsp;Mingli Xiang ,&nbsp;Linli Li","doi":"10.1016/j.ejmech.2025.117796","DOIUrl":"10.1016/j.ejmech.2025.117796","url":null,"abstract":"<div><div>Inflammatory programmed cell death mediated by NLRP3 inflammasome activation is one of the most representative forms of pyroptosis, involving multiple autoinflammatory diseases. In this investigation, we report the discovery of 3-pyridazinesulfonyl derivatives as a new class of inhibitors against NLRP3 inflammasome-dependent pyroptosis. We initially performed a phenotypic screening against NLRP3-dependent pyroptosis and discovered compound <strong>1 (Hit-1)</strong>, which showed moderate anti-pyroptotic activity (EC₅₀ = 10.977 ± 2.122 μM). Further structure-activity relationship (SAR) studies resulted in a novel potent compound <strong>32 (N102)</strong>, which exhibited an EC₅₀ of 0.029 ± 0.010 μM against cell pyroptosis induced by nigericin. <strong>N102</strong> displayed remarkable inhibitory activity against NLRP3-dependent activation of caspase-1 and the release of IL-1β in human THP-1 cell-derived macrophages. Mechanistically, <strong>N102</strong> disturbed the interaction of NLRP3 with the adaptor protein ASC and inhibited ASC oligomerization. Moreover, <strong>N102</strong> possesses favorable HLM stability (<em>T</em>_1/2 &gt; 120 min), low CYP3A4 inhibition (IC₅₀ &gt; 10 μM) and good permeability (Papp = 9.063 × 10⁻⁵ cm s⁻¹). Overall, we discovered a new potent small molecular inhibitor against NLRP3 inflammasome-dependent pyroptosis with potent cellular activity, favorable human-derived metabolic stability and permeability <em>in vitro</em>, which could be a good lead compound and deserves further in-depth studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117796"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164896","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":"Triptolide-based cleavable antibody-drug conjugates for pancreatic cancer","authors":"Huihui Wang ,&nbsp;Shangwei Huangfu ,&nbsp;Ding Wei ,&nbsp;Ziyu Sun ,&nbsp;Yifan Wu ,&nbsp;Xianqiang Yu ,&nbsp;Biao Jiang ,&nbsp;Hongli Chen","doi":"10.1016/j.ejmech.2025.117798","DOIUrl":"10.1016/j.ejmech.2025.117798","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) have emerged as a highly promising modality for the treatment of various tumors, including pancreatic cancer. Due to the modular nature of ADCs, their efficacy is heavily influenced by the choice of antibody, payload, and linker. Given the therapeutic potential of triptolide for pancreatic cancer, this study aims to harness triptolide as the cytotoxic payload to construct ADCs targeting pancreatic cancer. Silyl ethers were utilized for the first time as cleavable linkers to connect triptolide with an antibody. This is because silyl ethers can be easily synthesized and the rate of drug release can be regulated by modifying the silyl ether groups. The release profile of the resulting linkers was investigated. And considering the balance between cleavage and stability, one silyl ether-based linker was selected to prepare an ADC, named <strong>A10</strong>. Meanwhile, a traditional dipeptide linker-based ADC, <strong>A9</strong>, was synthesized for comparison. The ADC <strong>A10</strong> demonstrated superior inhibitory effects compared to ADC <strong>A9</strong>, both in vitro and in vivo. <strong>A10</strong> displayed targeted cytotoxicity against cells with high PD-L1 expression and demonstrated a bystander killing effect on cells with low PD-L1 expression. In vivo imaging studies indicated that fluorescently labeled <strong>A10</strong> accumulated in tumor regions. Additionally, significant antitumor activities of <strong>A10</strong> were observed against Panc 08.13-derived tumor xenografts.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"295 ","pages":"Article 117798"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164898","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":"Picomolar bivalent inhibitors of protein kinase CK2 active against β-coronavirus replication","authors":"Dylan Grenier ,&nbsp;Dennis Salomon Lopez Molina ,&nbsp;Muriel Gelin ,&nbsp;Angélique Mularoni ,&nbsp;Jean-François Guichou ,&nbsp;Jean-Guy Delcros ,&nbsp;Charlotte Martinasso ,&nbsp;Yinshan Yang ,&nbsp;Nazim Ahnou ,&nbsp;Jean-Michel Pawlotsky ,&nbsp;Abdelhakim Ahmed-Belkacem ,&nbsp;Isabelle Krimm","doi":"10.1016/j.ejmech.2025.117826","DOIUrl":"10.1016/j.ejmech.2025.117826","url":null,"abstract":"<div><div>The protein casein kinase 2 (CK2) has been shown to be upregulated in SARS-CoV-2 infections. However, few inhibitors have been tested for antiviral activity against coronaviruses. In this study, highly potent and selective bivalent inhibitors targeting the protein kinase CK2 were developed. The chemical structure of the well-known inhibitor CX-4945 was used as an anchor for the ATP-binding site and was linked by polar and aliphatic linkers to chemical structures that bind the cryptic αD pocket of CK2. The bivalent inhibitor <strong>Biv5</strong>, which demonstrated a sub-nanomolar kinase inhibition, showed potent antiviral activity against SARS-CoV-2 in HEK-ACE2-TMPRSS2 and Vero cells. In addition, <strong>Biv5</strong> significantly reduced viral replication over time in an ex vivo model of primary human nasal epithelial cells. The selectivity of <strong>Biv5</strong> was tested against 16 kinases targeted by CX-4945, confirming that targeting the αD pocket confers high selectivity for CK2 to such inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117826"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177129","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 indane and naphthalene derivatives as USP7 inhibitors","authors":"Xian Zhang ,&nbsp;Shudan Tan ,&nbsp;Dalin Wang ,&nbsp;Huayun Zhu ,&nbsp;Di Chen ,&nbsp;Yueting Chen ,&nbsp;Guangqing Wu ,&nbsp;Zhizhen Zhu ,&nbsp;Fengyi Zhang ,&nbsp;Zijiang Liang ,&nbsp;Li Xu ,&nbsp;Xing Li ,&nbsp;Haoliang Yuan ,&nbsp;Qinglong Xu ,&nbsp;Liang Dai ,&nbsp;Zhiqi Feng ,&nbsp;Caiping Chen ,&nbsp;Liu Liu ,&nbsp;Xiaoan Wen","doi":"10.1016/j.ejmech.2025.117824","DOIUrl":"10.1016/j.ejmech.2025.117824","url":null,"abstract":"<div><div>Protein deubiquitination via deubiquitinases is a crucial aspect of the dynamic modification of biomacromolecules. The deubiquitinase USP7 plays a key role in tumorigenesis through diverse pathways, thus representing a promising novel target for anti-cancer therapies. In this paper, in order to find novel USP7 inhibitors, a series of compounds scaffold-hopping from the reported USP7 inhibitor <strong>CP41</strong> were designed, synthesized and biologically evaluated. Most of them exhibited certain inhibition against the <em>in vitro</em> USP7 enzyme activity. The most potent compounds (<strong>X12</strong>, <strong>X16</strong>, <strong>X21</strong>, <strong>X22</strong> and <strong>X23</strong>) were highly selective for USP7 over a panel of other tested DUBs and showed significant <em>in vitro</em> inhibition against cancer cell proliferation. Interestingly, in RS4; 11 cancer cells, the selected compound <strong>X21</strong> not only regulated the level of the extensively studied proteins (<em>e.g.</em> MDM2, p53, TRIM27) but also remarkably reduced the protein level of PCLAF, a key factor involved in TLS. In colon cancer animal models, <strong>X21</strong> exerted <em>in vivo</em> anti-tumor efficacy, probably through synergistic effects of direct cytotoxicity and immune microenvironment improvement. These findings may provide directions for future design of novel USP7 inhibitors and facilitate the exploration of new mechanism of USP7 inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"295 ","pages":"Article 117824"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177132","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":"Development of a potent BET inhibitor for the treatment of renal fibrosis","authors":"Jianhang Huang ,&nbsp;Na Zhao ,&nbsp;Jian Li ,&nbsp;Jiayi Zhu ,&nbsp;Guoao Liang ,&nbsp;Xing Chen ,&nbsp;Naiyuan Wang ,&nbsp;Huilong Zhu ,&nbsp;Ningning Pang ,&nbsp;Chunmei An ,&nbsp;Xiaochun Xiong","doi":"10.1016/j.ejmech.2025.117822","DOIUrl":"10.1016/j.ejmech.2025.117822","url":null,"abstract":"<div><div>BRD4 serving as an attractive target for the treatment of renal fibrosis has recently received considerable attention. However, to date, the BRD4 inhibitors developed for renal fibrosis treatment were relatively few. Herein, we report the discovery of novel BRD4 inhibitors from virtual screening hit compound <strong>1</strong> with moderate inhibitory activity (IC₅₀ = 7.5 ± 2.9 μM). Through the medicinal chemistry optimization program, leading to the discovery of three potent BRD4 inhibitors, <strong>10</strong>, <strong>19</strong> and <strong>31</strong> with IC₅₀ values of 20.0 ± 7.1, 17.5 ± 6.4 and 13.5 ± 4.9 nM, respectively. Among them, <strong>31</strong> showed an acceptable liver microsomal stability and displayed a desired pharmacokinetic profile. Further, we confirmed the therapeutic efficacy of <strong>31</strong> in alleviating renal fibrosis on both UUO and folic acid (FA)-induced renal fibrosis mouse models. Collectively, our results indicated that compound <strong>31</strong> might be a promising candidate for renal fibrosis treatment and deserves further investigations.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"295 ","pages":"Article 117822"},"PeriodicalIF":6.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164899","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":"Mechanistic analysis of diverse click reactions along with their applications","authors":"Sushmita Bhatia ,&nbsp;Avadh Biharee ,&nbsp;Souren Mondal ,&nbsp;Swanand Kulkarni ,&nbsp;Rakesh Kumar ,&nbsp;Suresh Thareja","doi":"10.1016/j.ejmech.2025.117800","DOIUrl":"10.1016/j.ejmech.2025.117800","url":null,"abstract":"<div><div>The emergence of click chemistry has changed the face of chemical synthesis in the direction of modular, high-yielding, and greener reactions. The past two decades have evidenced a tremendous pace in the development of click chemistry and its applications in synthetic, pharmaceutical and allied sciences. Click chemistry shakes hands with green chemistry and enables chemists to dive deeper into newer chemical transformations with minimal harm caused to the environment. The present review describes the principles of click chemistry, its origin and innovations. Most relevant reactions within the click chemistry framework, including copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), strain-promoted azide-alkyne cycloaddition (SPAAC), and other crucial methodologies like thiol-ene reactions are discussed along with their mechanisms. Furthermore, applications of click chemistry have been discussed in pharmacotherapeutic and chemical aspects. These reactions have demonstrated unparalleled versatility across all areas of science due to their biocompatibility, efficiency and reliability, making them into the spotlight for discovering new drugs and optimizing them. Applications of click chemistry in the bio labeling mechanism as it precisely produces molecular images or diagnostics while undertaking proteomics and proteolysis-targeting chimeras (PROTACs) are also discussed. This holistic review follows the transformative influence of click chemistry through interdisciplinary fields. It sets the impetus for biomedical innovation, chemical biology innovation, and materials science innovation in biomedical research. With its modularity and robustness, click chemistry will continue to stretch the paradigms of synthetic and applied chemistry and may become indispensable in solving complex scientific challenges.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117800"},"PeriodicalIF":6.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164901","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 new celastrol derivatives with antitumor activity in vitro and in vivo by blocking Hsp90-Cdc37-kinase cycle","authors":"Lulu Zhang ,&nbsp;Jianbo Sun ,&nbsp;Junjie Wang,&nbsp;Yue Wang,&nbsp;Wei Ju,&nbsp;Yongqing Zhang,&nbsp;Na Li,&nbsp;Li Chen","doi":"10.1016/j.ejmech.2025.117827","DOIUrl":"10.1016/j.ejmech.2025.117827","url":null,"abstract":"<div><div>Hsp90-Cdc37-kinase cycle plays a critical role in the development of cancers. And the phosphorylation of Cdc37 (Serine13) by CK2 is a prerequisite. Celastrol (CEL) can interfere with Hsp90-Cdc37-kinase cycle by inhibiting Hsp90-Cdc37 protein-protein interaction (PPI) to exhibit antitumor effect. In this study, the pharmacophore of CK2 inhibitors was first introduced to CEL to obtain 18 derivatives to improve the antitumor activity, and the anti-proliferation of the derivatives was evaluated. Among them, compound <strong>11</strong> exhibited the most potent activity against MDA-MB-231 (IC₅₀ = 0.25 ± 0.02 μM) which was about 7 times that of CEL. Furthermore, <strong>11</strong> not only selectively inhibited CK2 activity, but also disrupted Hsp90-Cdc37 PPI, thereby leading to a sharp decrease on the level of kinase clients to arrest cell cycle and induce apoptosis. Moreover, <strong>11</strong> showed much higher tumor inhibition rate (65.3 %) than CEL (38.0 %) <em>in vi</em>vo without obvious toxicity. Taken together, compound <strong>11</strong> could more effectively block Hsp90-Cdc37-kinase cycle, which might be a promising antitumor candidate.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117827"},"PeriodicalIF":6.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164902","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 potent, broad-spectrum and in vivo effective deuterated tetrazole CYP51 inhibitor","authors":"Zirui Luo ,&nbsp;Rongrong Liu ,&nbsp;Yixiang Sun ,&nbsp;Leimeng Zhao ,&nbsp;Jiachen Zhang ,&nbsp;Kejian Li ,&nbsp;Zixuan Gao ,&nbsp;Nian Liu ,&nbsp;Haoyu Zhang ,&nbsp;Xudong Wu ,&nbsp;Jingming Liu ,&nbsp;Wenzhan Hao ,&nbsp;Xin Su ,&nbsp;Dongmei Zhao ,&nbsp;Maosheng Cheng","doi":"10.1016/j.ejmech.2025.117817","DOIUrl":"10.1016/j.ejmech.2025.117817","url":null,"abstract":"<div><div>Invasive fungal infections (IFIs) are a serious infectious disease worldwide, characterized by high mortality and morbidity. Azole drugs are the most commonly used drugs for the treatment of invasive fungal infections. However, because azole drugs can easily interact with human CYPs metabolic enzymes, the risk of drug-to-drug interaction is high when multiple drugs are used together with azole drugs in clinic. As the problem of fungal drug resistance is becoming increasingly serious, there is an urgent need to develop new CYP51 inhibitors. The successful marketing of Oteseconazole has brought the development of azole drugs into a new era. Compound <strong>A33</strong>, previously discovered by our group, showed excellent antifungal activity against a variety of pathogenic and drug-resistant fungi. Nevertheless, owing to its structural characteristics, it showed poor selectivity for the human CYPs family and extremely poor metabolic stability. To address the above problem, inspired by the reduced CYP inhibition observed in Oteseconazole, we replaced its triazole group with tetrazole and attempted deuteration strategies and carbonyl introduction to block the metabolic site. This modification led to the synthesis of compounds <strong>V01–V24</strong>, in which <strong>V23</strong> showed broad-spectrum activity and resistance characteristics, especially against <em>Aspergillus fumigatum</em> (MIC₈₀ = 1 <em>μ</em>g/mL), which had no inhibitory activity for many azole drugs. Compared to <strong>A33</strong>, the introduction of the tetrazole structure reduced its inhibitory activity against the human CYPs family. Furthermore, <strong>V23</strong> could prevent fungal phase transformation and biofilm formation, resulting in satisfactory fungicidal activity. <strong>V23</strong> showed negligible toxicity toward SH-SY5Y and HUVEC cells, <em>and in vivo</em> pharmacodynamic studies have shown that <strong>V23</strong> has significant <em>in vivo</em> antifungal activity. In conclusion, the discovery of compound <strong>V23</strong> is a successful exploration of a new tetrazole CYP51 inhibitor for the treatment of invasive fungal infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117817"},"PeriodicalIF":6.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164900","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":"How generative Artificial Intelligence can transform drug discovery?","authors":"Ainin Sofia Jusoh ,&nbsp;Muhammad Akmal Remli ,&nbsp;Mohd Saberi Mohamad ,&nbsp;Tristan Cazenave ,&nbsp;Chin Siok Fong","doi":"10.1016/j.ejmech.2025.117825","DOIUrl":"10.1016/j.ejmech.2025.117825","url":null,"abstract":"<div><div>Generative Artificial Intelligence (Generative AI) is transforming drug discovery by enabling advanced analysis of complex biological and chemical data. This review explores key Generative AI models, including Generative Adversarial Networks (GANs), Variational Autoencoders (VAEs), flow-based models and Transformer-based models, with Transformers gaining prominence due to the abundance of text-based biological data and the success of language models like ChatGPT. The paper discusses molecular representations, performance evaluation metrics, and current trends in Generative AI-driven drug discovery, such as protein-protein interactions (PPIs), drug-target interactions (DTIs) and de-novo drug design. However, these approaches face significant challenges, including applicability domain issues, lack of interpretability, data scarcity, novelty, scalability, computational resource limitations, and the absence of standardized evaluation metrics. These challenges hinder model performance, complicate decision-making, and limit the generation of novel and viable drug candidates. To address these issues, strategies such as hybrid models, integration of multiomics datasets, explainable AI (XAI) techniques, data augmentation, transfer learning, and cloud-based solutions are proposed. Additionally, a curated list of databases supporting drug discovery research is provided. The review concludes by emphasizing the need for optimized AI models, robust validation methods, interdisciplinary collaboration, and future academic efforts to fully realize the potential of Generative AI in advancing drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"295 ","pages":"Article 117825"},"PeriodicalIF":6.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145818","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 genipin derivatives as highly selective ferroptosis inducers for the treatment of triple-negative breast cancer","authors":"Jing-Wen Yu ,&nbsp;Yan Cao ,&nbsp;Ya-Zheng Zhu ,&nbsp;Zheng-Yu Hu ,&nbsp;Qing-Jia Ren ,&nbsp;Hui Miao ,&nbsp;Yong Yin ,&nbsp;Cao-Long Li","doi":"10.1016/j.ejmech.2025.117823","DOIUrl":"10.1016/j.ejmech.2025.117823","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is limited in treatment options due to the absence of three receptors, and evidence suggests that TNBC is sensitive to ferroptosis. In this study, a series of genipin derivatives were synthesized through a hybridization strategy that integrated the structures of RSL3 and ML162. Among these derivatives, compound <strong>B23</strong> demonstrated remarkable activity against the MDA-MB-231 cell line with an IC₅₀ value of 40 nM, significantly outperforming genipin, RSL3 and ML162. Furthermore, <strong>B23</strong> exhibited high selectivity for ferroptosis with a selectivity ratio of up to 108-fold. Further studies revealed that <strong>B23</strong> induces ferroptosis by affecting the expression of ferroptosis-related proteins ACSL4, GPX4, and FTH1, thereby disrupting intracellular iron homeostasis and the GSH/GPX4 antioxidant defense system, ultimately leading to the accumulation of lipid peroxidation (LPO). Animal model demonstrated that <strong>B23</strong> exhibited potent tumor suppression in an MDA-MB-231 xenograft model, achieving a tumor inhibition rate of 78.46 % at a dose of 4 mg/kg, without observable toxic side effects. In conclusion, <strong>B23</strong> represents a promising ferroptosis inducer for the treatment of TNBC and warrants further investigation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"295 ","pages":"Article 117823"},"PeriodicalIF":6.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145814","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}