European Journal of Medicinal Chemistry最新文献

{"title":"N-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides as novel multi-PI3K/DNA-PK/P-gp inhibitors for efficient chemosensitization and MDR alleviation","authors":"Martina Sukupova ,&nbsp;Karolina Knittelova ,&nbsp;Elham Parsimehr ,&nbsp;David Malinak ,&nbsp;Denisa Noskova ,&nbsp;Jana Kurcova ,&nbsp;Ester Marakova ,&nbsp;Zdenek Kratochvil ,&nbsp;Vladimir Pekarik ,&nbsp;Miroslav Psotka ,&nbsp;Jan Korabecny ,&nbsp;Ladislav Sivak ,&nbsp;Pavel Kulich ,&nbsp;Zbynek Heger ,&nbsp;Vojtech Adam ,&nbsp;Kamil Kuca","doi":"10.1016/j.ejmech.2025.117641","DOIUrl":"10.1016/j.ejmech.2025.117641","url":null,"abstract":"<div><div>PI3K signaling pathway is crucial for a plethora of cellular processes and is extensively linked with tumorigenesis and chemo-/radioresistance. Although a number of small molecule inhibitors have been synthesized to control PI3K-mediated signaling, only a limited clinical success has been reached. Thus, the search for novel promising candidates is still ongoing. Herein, we present a novel series of <em>N</em>-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides designed to simultaneously inhibit PI3K and DNA-PK activity. Compared to a commercial DNA-PK/PI3K inhibitor AZD7648, synthesized compounds generally exhibited markedly lower baseline cytotoxicity in all tested cell lines (MC38, B16F10, 4T1, CT26 and HEK-239). Through an array of biological experiments, we selected two most promising compounds, <strong><em>2</em></strong> and <strong><em>6</em></strong>. While in cell-free conditions, <strong><em>6</em></strong> acted as a very efficient pan-PI3K and DNA-PK inhibitor, in physiological conditions, <strong><em>2</em></strong> performed better and acted as a potent chemosensitizer able to increase the amount of DNA double strand breaks induced by doxorubicin. This was plausibly due to its improved ability to accumulate in nuclei as evidenced by confocal analyses. Importantly, using P-gp overexpressing CT26 cells, we found that <strong><em>2</em></strong> is an efficient inhibitor of multidrug resistance (MDR) able to down-regulate expression of mRNA encoding MDR-driving proteins ABCB1A, ABCB1B and ABCC1. We also demonstrate that <strong><em>2</em></strong> can be simply loaded into lipid nanoparticles that retain its chemosensitizing properties. Taken together, the presented study provides a solid basis for a subsequent rational structure optimization towards new generation of multitarget inhibitors able to control crucial signaling pathways involved in tumorigenesis and drug resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117641"},"PeriodicalIF":6.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831533","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":"A comprehensive review of small molecules, targets, and pathways in ulcerative colitis treatment","authors":"Xiao-Xuan Cai ,&nbsp;Yi-Han Huang ,&nbsp;Yang-Chi-Dung Lin ,&nbsp;Hsi-Yuan Huang ,&nbsp;Yi-Gang Chen ,&nbsp;Da-Peng Zhang ,&nbsp;Tao Zhang ,&nbsp;Yue Liu ,&nbsp;Hua-Li Zuo ,&nbsp;Hsien-Da Huang","doi":"10.1016/j.ejmech.2025.117645","DOIUrl":"10.1016/j.ejmech.2025.117645","url":null,"abstract":"<div><div>Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), poses significant clinical challenges because of its complex pathophysiology, long-term nature, and the limited efficacy of existing treatments. Small-molecule compounds, particularly those that are able to modulate inflammation-related signaling pathways and, in many cases, occur in nature, offer a promising alternative or supplement to conventional therapies. Studies on molecules for UC therapeutics reported in 1394 publications over the past 30 years were collected from the Web of Science (WOS) database. Only studies that verified therapeutic efficacy through animal experiments were included. Through an analysis of the molecular classes, structures, common targets, and pathways using network pharmacology, we identified 14 classes of compounds, 5 direct-target modules, and 3 crucial downstream pathways. Alkaloids, phenylpropanoids, flavonoids, and terpenes (and their derivatives) appeared most frequently and mainly targeted lipid metabolism, oxidative stress, immune regulation, signaling transduction, and cancer-related pathways. Notably, there has been an increasing trend of applying naturally sourced compounds in both preclinical and clinical trials, especially flavonoids, over the last five years. Although progress in UC research has been made, the majority of studies have focused on the overall therapeutic effects and biomarker alterations, with limited emphasis on the direct targets and underlying mechanisms. These findings highlight the need to explore novel small-molecule therapeutic strategies for UC, focusing on clearly defined targets and precise modes of action.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117645"},"PeriodicalIF":6.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837496","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 novel molecular glue degrader targeting GSPT1/2 with a non-IMiD-based CRBN binder","authors":"Seulki Park ,&nbsp;Akshay D. Takwale ,&nbsp;Ji-Eun Lee ,&nbsp;Namsik Yu ,&nbsp;Yong Hyo Kim ,&nbsp;Joo Youn Lee ,&nbsp;Yong Hee Cho ,&nbsp;Jin Hwa Cho ,&nbsp;Jeong Hee Moon ,&nbsp;Gaseul Lee ,&nbsp;Jung-Ae Kim ,&nbsp;Jong Yeon Hwang ,&nbsp;Jeong-Hoon Kim","doi":"10.1016/j.ejmech.2025.117642","DOIUrl":"10.1016/j.ejmech.2025.117642","url":null,"abstract":"<div><div>Targeting undruggable proteins by inducing proximity between E3 ligase and their substrates has emerged as an innovative strategy for tackling challenging diseases. In this study, we identified a novel GSPT1 degrader, <strong>4a</strong> (KMG-1068), through screening of our in-house small molecule library. Treatment with <strong>4</strong>a demonstrated significant anti-proliferative activity across multiple cell lines, which was diminished by co-treatment with MLN4924, suggesting the involvement of the Cullin-containing complex. Quantitative proteomic analysis indicated that <strong>4a</strong> predominantly induces the degradation of GSPT1/2. We further validated that <strong>4a</strong>-mediated GSPT1/2 degradation is dependent on both CUL4 and CRBN. Moreover, <strong>4a</strong> forms a ternary complex with CRBN and GSPT1/2, albeit with weaker binding affinity compared to reported GSPT1 molecular glues. BRET assays and competition assays with pomalidomide demonstrated that <strong>4a</strong> binds to the C-terminal IMiD binding site of CRBN, leading to the degradation of GSPT1. Despite lacking the characteristic glutarimide moiety present in other CRBN-based molecular glue degraders, <strong>4a</strong> interacts effectively with the IMiD binding site of CRBN. Structural characterization through analog synthesis further underscored the importance of specific structural features for CRBN engagement, GSPT1/2 degradation, and anti-proliferative effects, establishing <strong>4a</strong> as a promising novel GSPT1/2 degrader with significant therapeutic potential.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117642"},"PeriodicalIF":6.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831521","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 3,4-dihydropyrimidine derivatives as novel Anti-PEDV agents targeting viral internalization through a unique calcium homeostasis disruption mechanism","authors":"Sai Lv ,&nbsp;Rumeng Ma ,&nbsp;Qun Tang ,&nbsp;Xiaoyang Wang ,&nbsp;Chunmei Wang ,&nbsp;Keyu Zhang ,&nbsp;Houkai Li ,&nbsp;Wenchong Ye ,&nbsp;Wen Zhou","doi":"10.1016/j.ejmech.2025.117637","DOIUrl":"10.1016/j.ejmech.2025.117637","url":null,"abstract":"<div><div>Porcine epidemic diarrhea virus (PEDV) poses critical challenges to global swine production, with current vaccines showing limited efficacy against emerging strains. To address this gap, we designed 41 novel 3,4-dihydropyrimidine derivatives via systematic structure-activity relationship (SAR) optimization. Compound <strong>D39</strong>, incorporating a C-4 2′-substituted biphenyl, C-2 thione, C-6 phenyl, and C-5 isopropanol substituents, emerged as the most potent anti-PEDV agent (EC₅₀ = 0.09 μM, SI = 358.9), outperforming remdesivir (EC₅₀ = 3.14 μM, SI &gt; 40.8) by 35-fold. <strong>D39</strong> exhibited broad-spectrum anti-coronavirus activity (FIPV, IDV) at micromolar levels and demonstrated acceptable metabolic stability (T_1/2 = 78.75 min, Cl_int = 8.8 μL/min/mg) in porcine liver microsomes. Mechanistic studies revealed the antiviral actions was achieved by blocking PEDV early internalization via intracellular Ca²⁺ homeostasis modulation. These findings highlight <strong>D39</strong> as a first-in-class anti-PEDV candidate with a unique dihydropyrimidine scaffold and a calcium-targeting mechanism, offering a promising therapeutic strategy against coronaviral infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117637"},"PeriodicalIF":6.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837624","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":"Corrigendum to “Discovery of 3,5-diaryl-1H-pyrazol-based ureas as potent RET inhibitors” [Eur. J. Med. Chem. (2023), 251, 115237]","authors":"Kaifu Wu, Rui He, Zongyang Li, Kongxi Qiu, Guorong Xiao, Lijie Peng, Xiangbao Meng, Canhui Zheng, Zhang Zhang, Qian Cai","doi":"10.1016/j.ejmech.2025.117581","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117581","url":null,"abstract":"The authors regret that there was an inadvertent misplacement of protein bands in Fig. 5 during the initial drafting process, resulting in the duplication of SHC protein bands.<span><figure><span><img alt=\"Fig. 5\" aria-describedby=\"cap0010\" height=\"391\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523425003460-fx1.jpg\"/><ol><li><span><span>Download: <span>Download high-res image (844KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span><span><span><p><span>Fig. 5</span>. In the manuscript (The bands in red frame were wrongly copied.).</p></span></span></figure></span><span><figure><span><img alt=\"Fig. 5\" aria-describedby=\"cap0015\" height=\"379\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523425003460-fx2.jpg\"/><ol><li><span><span>Download: <span>Download high-res image (853KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span><span><span><p><span>Fig. 5</span>. Corrected figure.</p></span></span></figure></span>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"60 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831536","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":"A novel liver-targeted and highly selective fluorescent probe for hepatic hydrogen sulfide detection in the diagnosis of drug-induced liver injury","authors":"Yalin Li,&nbsp;Bill Zhereng Liao,&nbsp;Qimei Tan,&nbsp;Jiangmin Zhu,&nbsp;Ling Zhu,&nbsp;Lihong Hong,&nbsp;Chen Chen,&nbsp;Feiyan Liu,&nbsp;Lingyi Kong,&nbsp;Jianguang Luo","doi":"10.1016/j.ejmech.2025.117640","DOIUrl":"10.1016/j.ejmech.2025.117640","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) has emerged as a significant health risk, yet reliable methods of detection at an early stage are in urgent need. Recent researches have highlighted the crucial role of hydrogen sulfide (H₂S) in various pathological and physiological processes, with a correlation between its levels and the severity of DILI. We developed a novel fluorescent probe <strong>H₂S-YL</strong> for the precise detection of liver H₂S fluctuations in DILI, and the liver <em>in situ</em> accumulation capacity of <strong>H₂S-YL</strong> has been significantly enhanced by incorporating a liver-targeting cholic acid moiety into its skeleton. Furthermore, <strong>H₂S-YL</strong> displays exceptional selectivity, good sensitivity and responds rapidly toward H₂S within 3 min, thereby enabling precise detection of subtle hepatic H₂S fluctuations capability essential for accurately assessing the severity of DILI. Subsequently, <strong>H₂S-YL</strong> was employed to assess the hepatoprotective effects of natural constituents derived from traditional Chinese medicine, via monitoring H₂S levels both in cells and <em>in vivo</em>. These results demonstrate that <strong>H₂S-YL</strong> serves as a powerful tool for visualizing pathological hepatic H₂S fluctuations, thereby enabling the assessment of DILI severity and the efficacy of hepatoprotective natural constituents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117640"},"PeriodicalIF":6.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831594","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":"Potential therapeutic targets of eukaryotic translation initiation factors in tumor therapy","authors":"Yujie Zhang ,&nbsp;Tianyou Liu ,&nbsp;Pengyu Li ,&nbsp;Zhichao Xing ,&nbsp;Li Mi ,&nbsp;Ting He ,&nbsp;Tao Wei ,&nbsp;Wenshuang Wu","doi":"10.1016/j.ejmech.2025.117638","DOIUrl":"10.1016/j.ejmech.2025.117638","url":null,"abstract":"<div><div>Translation initiation is the first and rate-limiting step in protein synthesis, and its dysregulation is frequently observed in various malignancies. Cap-dependent translation, the predominant form of translation initiation, relies on the coordinated action of eukaryotic translation initiation factors (eIFs), including eIF1, eIF2, eIF4, and others. These factors play critical roles in regulating the efficiency and fidelity of protein synthesis, and their overexpression has been linked to tumor progression, proliferation, and metastasis. Notably, certain eIFs have emerged as potential prognostic markers due to their elevated expression in tumors. Targeting eIFs represents a promising strategy, particularly for cancers characterized by aberrant eIF activity. In this review, we summarize the roles of individual eIFs in cap-dependent translation and discuss their potential as therapeutic targets in cancer treatment. We also highlight recent advances in drug discovery efforts aimed at modulating eIF activity, providing insights into the development of novel anticancer therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117638"},"PeriodicalIF":6.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831522","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":"Metronidazole-ursodeoxycholic acid bifunctional antibacterial: A promising strategy to combat Clostridium difficile infection and prevent recurrence","authors":"Kun Shi ,&nbsp;Li Wang ,&nbsp;Xiao-Min Zheng ,&nbsp;Zhe Zhang ,&nbsp;Fan Zhong ,&nbsp;Zhen-Zhu Sun ,&nbsp;Mohamed Mohany ,&nbsp;Hai-Hui Huang ,&nbsp;Jing Li ,&nbsp;Shan Li ,&nbsp;Lei Zhang","doi":"10.1016/j.ejmech.2025.117631","DOIUrl":"10.1016/j.ejmech.2025.117631","url":null,"abstract":"<div><div>Current treatments against <em>Clostridium difficile</em> infection (CDI), such as vancomycin and metronidazole, frequently lead to severe recurrence due to disruption of gut microbiota balance, which results in a pressing need for new chemical entities to treat CDI. Bile acids, such as UDCA, have been demonstrated to inhibit the growth and spore germination of <em>C. difficile</em>, and regulate the structure of the intestinal flora. This study involved the synthesis of eight bile acid-metronidazole hybrids. Among them, the most promising hybrid, <strong>SCUT1-2</strong>, effectively killed the vegetative cells of <em>C. difficile</em> with a minimum inhibitory concentration (MIC) of 0.06–0.50 μg/mL, and inhibited spore germination <em>in vitro</em>. The absolute bioavailability of SCUT1-2 (<em>F</em> = 56.8 %) indicated that approximately half of <strong>SCUT1-2</strong> was absorbed systemically, while a considerable portion remained in the gastrointestinal tract in its original form, laying a solid foundation for its effective action <em>in vivo</em>. <strong>SCUT1-2</strong> could effectively alleviate the symptoms of weight loss and diarrhea in mice caused by CDI and effectively reduce the relevant expressions of inflammatory factors, outperforming metronidazole. Furthermore, <strong>SCUT1-2</strong> demonstrated a favorable therapeutic effect in reducing mortality and disease symptoms in CDI mice by killing <em>C. difficile</em> cells and regulating the composition and structure of the intestinal flora. Notably, <strong>SCUT1-2</strong> could effectively prevent recurrent CDI. This work provides a potential clinical lead for the development of CDI therapies and highlights hybrid medication as a new strategy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117631"},"PeriodicalIF":6.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828668","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":"Clinically approved small-molecule drugs for anemia therapy","authors":"Yang Wang ,&nbsp;Wancheng Zhao ,&nbsp;Shenshen Yao ,&nbsp;Sha Ni,&nbsp;Chong Feng,&nbsp;Dan Wang","doi":"10.1016/j.ejmech.2025.117623","DOIUrl":"10.1016/j.ejmech.2025.117623","url":null,"abstract":"<div><div>Anemia, a common blood disorder characterized by reduced red blood cell or hemoglobin levels, affects a significant portion of the global population. Traditional treatments, including dietary supplements and blood transfusions, often fail to address the underlying causes of anemia, particularly in chronic or genetic forms. This review highlights representative small-molecule drugs approved for anemia treatment, focusing on their synthetic routes and clinical applications. The synthetic routes of these drugs, often involving advanced organic chemistry techniques are crucial for optimizing production efficiency and scalability. Clinically, these small-molecule drugs have shown broad-spectrum therapeutic potential, with applications extending to various forms of anemia. This review underscores the importance of understanding the synthetic pathways of these drugs, which not only facilitates industrial-scale production but also paves the way for the development of next-generation therapies. Future research is expected to further optimize these small-molecule drugs, potentially leading to more effective and accessible treatments for anemia.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117623"},"PeriodicalIF":6.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828726","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 PI3KC2γ inhibitors with high potency, selectivity, and favorable pharmacokinetics for glycogen metabolism regulation","authors":"Yi Zhong ,&nbsp;Peili Jiao ,&nbsp;Yuxi Wang ,&nbsp;Beibei Mao,&nbsp;Han Huang,&nbsp;Cheng Shi,&nbsp;Xiaojiao Sun,&nbsp;Zhenming Liu,&nbsp;Liangren Zhang","doi":"10.1016/j.ejmech.2025.117621","DOIUrl":"10.1016/j.ejmech.2025.117621","url":null,"abstract":"<div><div>Phosphatidylinositol 3-kinase Class IIγ (PI3KC2γ) is a critical regulator of PI(3,4)P₂ production on endosomal membranes, linking its activity to metabolic disorders such as diabetes, glycogen storage diseases, and hyperlipidemia. Despite its importance, selective inhibitors targeting PI3KC2γ remain underexplored. In this study, we developed novel scaffolds for PI3KC2γ inhibitors using structure-based design. A series of inhibitors were synthesized, among which compound <strong>23</strong> was identified as the most potent PI3KC2γ inhibitor reported to date. Functional assays confirmed that compound <strong>23</strong> effectively inhibits insulin-stimulated PI(3,4)P₂ formation, blocks glucose-to-glycogen conversion, and reduces excessive liver glycogen accumulation by downregulating the Akt2-glycogen synthase pathway. This study highlights the therapeutic potential of PI3KC2γ inhibition in glycogen storage diseases and provides efficient tool molecules for further drug development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117621"},"PeriodicalIF":6.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831535","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}