European Journal of Medicinal Chemistry最新文献

{"title":"Structural simplification of quaternary benzophenanthridine alkaloids generating a candidate for the treatment of non-small cell lung cancer","authors":"Qianhe Xu ,&nbsp;Pei Liu ,&nbsp;Qiuying Nie ,&nbsp;Yajun Chu ,&nbsp;Xiaojun Yao ,&nbsp;Jianguo Fang ,&nbsp;Junmin Zhang","doi":"10.1016/j.ejmech.2025.117551","DOIUrl":"10.1016/j.ejmech.2025.117551","url":null,"abstract":"<div><div>Quaternary benzophenanthridine alkaloids (QBAs), such as sanguinarine, chelerythrine, and nitidine, possess diverse pharmacological activities. This study presents a simplified structure for QBAs, yielding twelve three-membered phenanthridine alkaloids. Notably, compound <strong>6f</strong> demonstrates enhanced potency in selectively inhibiting thioredoxin reductase (TrxR, <em>TXNRD</em>) and exhibits significant cytotoxicity against non-small cell lung cancer (NSCLC) cells. While TrxR is a selenoenzyme, many of its inhibitors react with biological thiols; however, <strong>6f</strong> shows minimal reactivity with thiols such as glutathione (GSH) and cysteine. Mechanistic investigations reveal that <strong>6f</strong> stimulates reactive oxygen species production, reduces intracellular thiols, and decreases the GSH/GSSG ratio, leading to cell apoptosis through oxidative stress. Moreover, significant tumor regression has been observed in nude mice with NSCLC following treatment with <strong>6f</strong>. The pronounced anticancer activity and possible mechanism of action of <strong>6f</strong> suggest its potential as a candidate for further development in NSCLC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117551"},"PeriodicalIF":6.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675329","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":"Tetracationic tetraaryltetranaphtho[2,3]porphyrins for photodynamic inactivation against Staphylococcus aureus biofilm","authors":"Le Mi ,&nbsp;Tao Xu ,&nbsp;Ying-Yuan Peng ,&nbsp;Marina G. Strakhovskaya ,&nbsp;Yi-Jing Zhang ,&nbsp;Gennady A. Meerovich ,&nbsp;Tebello Nyokong ,&nbsp;Yi-Jia Yan ,&nbsp;Zhi-Long Chen","doi":"10.1016/j.ejmech.2025.117558","DOIUrl":"10.1016/j.ejmech.2025.117558","url":null,"abstract":"<div><div>Antimicrobial photodynamic therapy (aPDT) has emerged as a promising strategy for addressing bacterial infections, particularly those involving biofilm formation. The electrostatic attraction between the negatively charged bacterial cell walls and the cationic charges of photosensitizers facilitates the accumulation of PSs on bacterial surfaces, thereby enhancing aPDT efficacy. In this study, three series of tetracationic tetraaryltetranaphtho[2,3]porphyrins (TNPs), each incorporating different cationic groups with alkyl chains of varying lengths, were designed and synthesized. Their photodynamic inactivation efficacy against <em>S. aureus</em>, <em>E. coli and C. albicans</em> was evaluated, respectively. These TNPs exhibited strong absorption at ∼730 nm with high molar extinction coefficients (&gt;51,500 L·mol⁻¹·cm⁻¹), fluorescence emission at ∼758 nm and efficient singlet oxygen generation capabilities. Among them, TNPs with shorter alkyl chains (<strong>I₁, II₁</strong> and <strong>Ⅲ₁</strong>) exhibited enhanced phototoxicity against planktonic microbes, with <strong>I₁</strong> (containing pyridinium substituents) showing the highest activity. These three compounds effectively disrupted mature <em>S. aureus</em> biofilms, with <strong>Ⅲ₁</strong> (bearing diethylmethylammonium groups) demonstrating superior biofilm eradication capabilities. These findings highlight the dual antibacterial and biofilm-disrupting potential of these Ar₄TNP derivatives. Furthermore, their selective toxicity toward bacterial cells over mammalian cells at therapeutic doses provides a foundation for developing safer antimicrobial agents, offering promising alternatives to antibiotics for tackling drug-resistant pathogens and persistent biofilm-associated infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117558"},"PeriodicalIF":6.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in medicinal chemistry strategies for the development of METTL3 inhibitors","authors":"Gengwu Li ,&nbsp;Wei Chen ,&nbsp;Dan Liu ,&nbsp;Shibing Tang","doi":"10.1016/j.ejmech.2025.117560","DOIUrl":"10.1016/j.ejmech.2025.117560","url":null,"abstract":"<div><div><em>N</em>⁶-methyladenosine (m6A), the most abundant RNA modification in eukaryotic cells, exerts a critical influence on RNA function and gene expression. It has attracted considerable attention within the rapidly evolving field of epitranscriptomics. METTL3 is a key enzyme for m6A modification and is essential for maintaining normal m6A levels. High expression of METTL3 is closely associated with various cancers, including gastric cancer, liver cancer, and leukemia. Inhibiting METTL3 has shown potential in slowing cancer progression, thereby driving the development of METTL3 inhibitors. In this work, we summarize recent advancements in the development of METTL3 inhibitor, with a focus on medicinal chemistry strategies employed during discovery and optimization phases. We explore the application of structure-activity relationship (SAR) studies and protein-targeted degradation techniques, while addressing key challenges associated with their characterization and clinical translation. This review underscores the therapeutic potential of METTL3 inhibitors in modulating epitranscriptomic pathways and aims to offer perspectives for future research in this rapidly evolving field.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117560"},"PeriodicalIF":6.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675327","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 azetidine-based imidazopyridines as selective and orally bioavailable inhibitors of phosphodiesterase 10A for the treatment of pulmonary arterial hypertension","authors":"Hongzhe Huang ,&nbsp;Huanxin Xue ,&nbsp;Anqi Cai ,&nbsp;Han Yuan ,&nbsp;Yufen Yao ,&nbsp;Runduo Liu ,&nbsp;Yi Yang ,&nbsp;Quan Wang ,&nbsp;Zhe Li ,&nbsp;Ting Liu ,&nbsp;Yi-You Huang ,&nbsp;Wei Dai ,&nbsp;Hai-Bin Luo ,&nbsp;Xiaozhou Zou ,&nbsp;Xiaoying Wang ,&nbsp;Lei Guo","doi":"10.1016/j.ejmech.2025.117537","DOIUrl":"10.1016/j.ejmech.2025.117537","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a chronic, progressive disorder of the pulmonary vasculature characterized by associated pulmonary and cardiac remodeling. Phosphodiesterase 10A (PDE10A) plays a crucial role in regulating cAMP concentration, thereby influencing pulmonary inflammation and pulmonary vascular remodeling. However, there is a lack of ideal PDE10A selective inhibitors available for PAH treatment. Herein, we employed structure-based drug design to develop a series of azetidine-based imidazopyridines, among which <strong>A30</strong> demonstrated an IC₅₀ value of 3.5 nmol/L against PDE10A with high selectivity over other PDEs, low blood-brain barrier permeability, and improved drug-like properties. Oral administration of <strong>A30</strong> exhibited significant anti-PAH effects not only in monocrotaline-induced rats, but also in Sugen/hypoxia(Su/Hx)-induced PH mice. Our findings indicate that <strong>A30</strong> inhibits PDE10A to suppress pulmonary vascular remodeling through the activation of cAMP-associated signaling pathways.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117537"},"PeriodicalIF":6.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675272","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":"Semisynthesis and biological evaluation of 17-hydroxybrevianamide N derivatives as anti-inflammatory agents by mediating NF-κB and MAPK signaling pathways","authors":"Tian-Yi Zhou ,&nbsp;Yang-Yang Guo ,&nbsp;Qian-Qian Jing ,&nbsp;Mei-Yan Wei ,&nbsp;Wei-Feng Xu ,&nbsp;Yu-Cheng Gu ,&nbsp;Chang-Lun Shao","doi":"10.1016/j.ejmech.2025.117541","DOIUrl":"10.1016/j.ejmech.2025.117541","url":null,"abstract":"<div><div>Chronic inflammation is a trigger for many diseases that affect approximately 10–20 % of the population around the world. Herein, (±)-17-hydroxybrevianamide N (<strong>1</strong>) was isolated from the fungus <em>Aspergillus</em> sp. (CHNSCLM-0151) and exhibited strong inhibitory activity against nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cell. A series of new derivatives (±)<strong>-3</strong>−(±)<strong>-29</strong> was semisynthesized by structural modification of the imide, phenolic hydroxyl, and carbonyl groups from the natural product (±)-<strong>1</strong>. The results of anti-inflammatory activity demonstrated that (±)<strong>-4</strong>, (±)-<strong>6</strong>, (±)-<strong>9</strong>, (±)-<strong>22</strong>, (±)-<strong>23</strong>, and (±)-<strong>24</strong> exhibited obviously NO inhibitory (<em>P</em> &lt; 0.0001) in LPS-stimulated RAW264.7 cells. To further investigate the relationship between chirality and activity, the enantiomers of the above six compounds were obtained by chiral resolution. As expected, the bioactivity results indicated stereoselectivity in the anti-inflammatory effect among the different isomers. In particular, compound (+)-4<em>S</em>-<strong>23</strong> inhibited NO concentration with an IC₅₀ value of 0.5 μM, demonstrating 3-fold greater potency compared to its (<em>R</em>)-enantiomer, and achieving 40-fold superior potency over the positive control NG-monomethyl-<span>l</span>-arginine (L-NMMA). This compound demonstrated suppression of TNF-α (25.7 ± 1.5 %), IL-6 (54.5 ± 3.9 %) and IL-1β (92.9 ± 4.1 %) production at 2 μM. More importantly, mechanistic investigations revealed that (+)-4<em>S</em>-<strong>23</strong> (0.2 μM) modulates the MAPK signaling pathway, specifically downregulating phosphorylation of p38, ERK, and JNK. Furthermore, (+)-4<em>S</em>-<strong>23</strong> also exhibited potent inhibitory activity against the NF-κB pathway by suppressing the phosphorylation of IκB-α and blocking nuclear translocation of phosphorylated p65. Notably, these findings position (+)-4<em>S</em>-<strong>23</strong> as a promising candidate for development as a novel anti-inflammatory therapeutic targeting both MAPK and NF-κB signaling nodes.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117541"},"PeriodicalIF":6.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675325","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 rigid STING PROTAC degraders as potential therapeutics for acute kidney injury","authors":"Rongxiang Ma ,&nbsp;Renquan Fu ,&nbsp;Yifan Wang ,&nbsp;Kabonde Makasa Njobvu ,&nbsp;Yapeng Fan ,&nbsp;Zichao Yang ,&nbsp;Mingbing Chen ,&nbsp;Feifei Liu ,&nbsp;Zhongping Jiang ,&nbsp;Yong Rao ,&nbsp;Ling Huang ,&nbsp;Congjun Xu ,&nbsp;Jianjun Chen ,&nbsp;Jin Liu","doi":"10.1016/j.ejmech.2025.117539","DOIUrl":"10.1016/j.ejmech.2025.117539","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a critical condition resulting from intrinsic immune overactivation for which no ideal therapeutic agent is available. The development of therapeutic drugs with new targets and mechanism has become one of the important challenges in the pharmaceutical field. The interferon gene stimulating protein (STING) directly regulates the intrinsic immune processes and is a potential target for AKI therapy. Herein, we designed synthesized and evaluated a series of novel STING-PROTAC degraders <em>via</em> a rigid strategy. Among them, compound <strong>ST9</strong> performed the highest degradation capacity with a DC₅₀ of 0.62 μM in THP-1 cells. In a cisplatin-induced HK-2 cell model, <strong>ST9</strong> could down-regulate the STING/NF-κB signaling axis and thus inhibit the expression of inflammatory factors. Additionally, <strong>ST9</strong> showed a significantly improved metabolic stability profile. Furthermore, <strong>ST9</strong> displayed favorable <em>in vivo</em> anti-AKI efficacy and has no toxic side effects on other organs. These results suggest that the novel rigid STING-PROTAC <strong>ST9</strong> has clinical potential as a renoprotective agent for the treatment/prevention of acute kidney injury.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117539"},"PeriodicalIF":6.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675326","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":"Role of quercetin as a promising antiviral, therapeutic and immunomodulatory mediator against dengue virus induced robust infection in in-vivo Balb/C mice model","authors":"Saikat Mukherjee,&nbsp;Anusri Tripathi","doi":"10.1016/j.ejmech.2025.117536","DOIUrl":"10.1016/j.ejmech.2025.117536","url":null,"abstract":"<div><div>Currently, there are no clinically approved antiviral agents against dengue-virus (DENV). This study aimed to determine the prophylactic, antiviral, and therapeutic potential of quercetin by its pre-treatment, co-treatment, and post-treatment [24, 48, and 72 h-post-infection (HPI)] of DENV-infected Balb/C mice through both oral and intraperitoneal (I.P) route, respectively. 80 mg/kg/day and 16 mg/kg/day of quercetin were non-toxic for oral and I.P administration, respectively. I.P. was found to be more effective than oral administration which significantly reduced DENV copy-number in co-treatment group (from day 1, <em>p</em> &lt; 0.01); post-treatment (24hpi),and pretreatment groups (day 3 onwards, <em>p</em> &lt; 0.05). Molecular-docking experiments indicated quercetin could act as a double-edged sword by strongly interacting with DENV envelope-glycoprotein (−8.1 kcal/mol) and NS5-RdRp domain (−8.0 kcal/mol), which are crucial for viral-attachment and replication. MD-simulation of docked complexes indicated their stability defined by low RMSD, RMSF, and stable H-bond with active-site residues. Significant reduction (<em>p</em> &lt; 0.001) in TNF-α, IL-6, ROS-production, and vascular leakage was observed among pre-, co-, and post-treatment (24 and 48 HPI) groups with promising hepatic and renal-protective effects. Pharmacological and functional-molecular interaction networks indicate a significant effect of quercetin on vascular integrity byVEGF-KDR signaling pathway (via PI3K-Akt and Ras signalling), oxygen homeostasis through HIF-1 signalling, and the anti-inflammatory response via PI3K-Akt, IL-6 and its receptor signalling (PPI enrichment P = 3.19e-10).Thus, it can be concluded that I.P. co- and post-treatment (24hpi) of quercetin to DENV-infected mice could effectively reduce viral-titer, pro-inflammatory cytokines, ROS-response, and vascular permeability. Taken together this demonstrates quercetin as an important antiviral candidate against dengue.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117536"},"PeriodicalIF":6.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665991","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":"The Liebeskind–Srogl cross-coupling reaction towards the synthesis of biologically active compounds","authors":"Jan Chasák,&nbsp;Ignacy Janicki,&nbsp;Lucie Brulíková","doi":"10.1016/j.ejmech.2025.117526","DOIUrl":"10.1016/j.ejmech.2025.117526","url":null,"abstract":"<div><div>In this review, we emphasize the significance of the Liebeskind-Srogl cross-coupling reaction, a palladium-catalyzed process involving the reaction between a thioester and a boronic acid. This reaction has emerged as a fundamental technique in synthetic methodologies aimed at the development of biologically active compounds. The Liebeskind-Srogl cross-coupling method has become an essential approach in chemistry, facilitating the diversification of complex structures that would be significantly more challenging to synthesize through alternative approaches. In this review, we aim to outline the numerous possibilities for preparing a wide range of derivatives, each with notable biological potential.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117526"},"PeriodicalIF":6.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665990","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":"Pharmacological advances and therapeutic applications of niclosamide in cancer and other diseases","authors":"Umm E. Laila,&nbsp;Zi-long Zhao,&nbsp;Da-Yu Xu,&nbsp;Huai Liu,&nbsp;Zhi-Xiang Xu","doi":"10.1016/j.ejmech.2025.117527","DOIUrl":"10.1016/j.ejmech.2025.117527","url":null,"abstract":"<div><div>Niclosamide, an FDA-approved drug traditionally used to treat parasitic infections, has garnered remarkable attention for its diverse pharmacological properties, suggesting potential therapeutic utility in oncology and a range of other diseases. This review offers an in-depth analysis of the chemical features and pharmacokinetics of niclosamide, underscoring the role of its salt forms and derivatives in enhancing bioavailability and therapeutic effectiveness. Emerging breakthroughs in nanotechnology have enabled the generation of advanced formulations capable of improving the safety and efficacy of niclosamide, addressing the challenges posed by its poor water solubility. Further, the review explores the intriguing molecular mechanisms driving niclosamide anticancer activity, highlighting its ability to act as a potent mitochondrial uncoupler and precisely modulate critical signal pathways that regulate cell proliferation, apoptosis, and inflammation. In cancer treatment, niclosamide has showcased compelling effects against various malignancies, offering marked potential in overcoming multidrug resistance, particularly in the resistant forms of leukemia and ovarian cancer. Additionally, the drug's versatility broadens its therapeutic potential beyond oncology, encompassing viral infections, metabolic disorders, and anti-inflammatory applications. By integrating the current literature, this review seeks to illuminate the pharmacological and clinical progress of niclosamide, hence emphasizing its promise as a multi-targeted therapeutic agent. As research evolves, niclosamide is poised to play a pivotal role in cancer therapy and the treatment of other complex diseases, reinforcing the necessity for continued clinical exploration and innovation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117527"},"PeriodicalIF":6.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of 3-amino-6-(2-hydroxyphenyl)pyridazin-4-aryl derivatives as SMARCA2/4 degraders","authors":"Tianqiong Yang ,&nbsp;Wei Wei ,&nbsp;Qi Zhang ,&nbsp;Xin Chen ,&nbsp;Kaiyan Xu ,&nbsp;Xingping Su ,&nbsp;Lin Yue ,&nbsp;Jiuyu Gao ,&nbsp;Ningyu Wang ,&nbsp;Yu Cao ,&nbsp;Luoting Yu ,&nbsp;Zhihao Liu","doi":"10.1016/j.ejmech.2025.117521","DOIUrl":"10.1016/j.ejmech.2025.117521","url":null,"abstract":"<div><div>SMARCA2/4, a pair of mutually exclusive core catalytic subunits of the chromatin remodeling complex SWI/SNF, play essential roles in regulating gene transcription. Given the pivotal role of SMARCA2/4 in sustaining the oncogenic transcription program and promoting proliferation in acute myeloid leukemia (AML), the development of non-selective degraders holds practical therapeutic implications. Herein, we designed and synthesized a series of proteolysis-targeting chimeras (PROTACs) by conjugating the VHL ligand to a SMARCA2/4 bromodomain ligand, 2-(6-amino-5-phenylpyridazin-3-yl)phenol, using various linkers. Preliminary evaluations identified <strong>A11</strong> as the most potent molecule that efficiently degraded SMRACA2 (DC₅₀ = 3.0 nM, D_max = 98 %) and SMARCA4 (DC₅₀ = 4.0 nM, D_max = 98 %). <strong>A11</strong> significantly inhibited the proliferation of hematological cancer cell lines, including MV-4-11, MOLM-13 and SU-DHL-4. It decreased the levels of SMARCA2/4 through the ubiquitin-proteasome system. Global proteome analysis revealed that <strong>A11</strong> was able to selectively target and degrade SMARCA2/4. Additionally, <strong>A11</strong> caused cell cycle arrest at the G0/G1 phase and induced cell apoptosis in MV-4-11 and MOLM-13 cells. It also blocked the oncogenic activity of <em>MYC</em> and other disease-related genes in AML cells. Overall, our data clarified that <strong>A11</strong> is a promising SMARCA2/4 degrader for cancer therapy, which is worthy of further evaluation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117521"},"PeriodicalIF":6.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660833","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}