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

Deuterium substitution at the intolerable site as a strategy to mitigate the toxicity of camptothecin derivatives 在难以忍受的部位氘取代作为减轻喜树碱衍生物毒性的策略

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-17 DOI: 10.1016/j.ejmech.2025.117877

Xianqiang Yu , Ziyu Sun , Jing Liu , Shangwei Huangfu , Qi Cheng , Jiakang Chen , Xiaobao Yang , Biao Jiang , Hongli Chen

{"title":"Deuterium substitution at the intolerable site as a strategy to mitigate the toxicity of camptothecin derivatives","authors":"Xianqiang Yu , Ziyu Sun , Jing Liu , Shangwei Huangfu , Qi Cheng , Jiakang Chen , Xiaobao Yang , Biao Jiang , Hongli Chen","doi":"10.1016/j.ejmech.2025.117877","DOIUrl":"10.1016/j.ejmech.2025.117877","url":null,"abstract":"<div><div>Camptothecin (CPT) is characterized by a planar fused-ring system consisting of five-membered rings. Structure-activity relationship studies have demonstrated that introducing a substituent at the C-5 position of CPT can disrupt its planar structure, leading to a decrease in its biological activity. In this study, a straightforward hydrogen-deuterium exchange method was developed to achieve bis-deuterium substitution at the C-5 position of CPT. The method was successfully extended to a series of CPT analogues. <em>In vitro</em> biological activity studies demonstrated that deuterium substitution effectively preserves the pharmacological function of CPT analogues. Pharmacokinetic studies indicated that the deuterated analogue of topotecan (TOP), named as TOP-2D, exhibits a shorter half-life (T<sub>1/2</sub>) and greater bioavailability (F%) compared to TOP when administered intraperitoneally (IP). Moreover, <em>in vivo</em> studies on antitumor activity showed that TOP-2D effectively inhibited tumor growth while having a minimal impact on the body weight of mice. In contrast, when administered via the same IP route and at the same dose, treatment with TOP caused a significant decrease in body weight. This reduced toxicity is likely attributable to deuteration, which promotes more rapid clearance of the drug and decreases metabolism-mediated toxicity, resulting in a safer profile.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117877"},"PeriodicalIF":6.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312231","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}

引用次数: 0

Corrigendum to “Design and development of chromene-3-carboxylate derivatives as antidiabetic agents: Exploring the antidiabetic potential via dual inhibition of angiotensin II type 1 receptor and neprilysin enzyme” [Europ. J. Med. Chem. 293 (2025) 117705] “作为降糖药的3-羧酸铬衍生物的设计和开发：通过双重抑制血管紧张素II型受体和neprilysin酶来探索降糖药的潜力”[欧洲]。医学化学杂志。293 (2025)117705]

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-16 DOI: 10.1016/j.ejmech.2025.117772

Shikha Thakur, Sandhya Chahal, Madhav S. Jadhav, Priyanka Mohanty, Anil Bhanudas Gaikwad, Jayant Sindhu, Hemant R. Jadhav

引用次数: 0

The physicochemical and biochemical mechanisms of porphyrinoid-mediated radiodynamic therapy 卟啉介导放射动力治疗的理化生化机制

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-16 DOI: 10.1016/j.ejmech.2025.117861

Sofia Leo , Nazareth Milagros Carigga Gutierrez , Anne-Laure Bulin , Jean-Luc Coll , Lucie Sancey , Benoit Habermeyer , Mans Broekgaarden

{"title":"The physicochemical and biochemical mechanisms of porphyrinoid-mediated radiodynamic therapy","authors":"Sofia Leo , Nazareth Milagros Carigga Gutierrez , Anne-Laure Bulin , Jean-Luc Coll , Lucie Sancey , Benoit Habermeyer , Mans Broekgaarden","doi":"10.1016/j.ejmech.2025.117861","DOIUrl":"10.1016/j.ejmech.2025.117861","url":null,"abstract":"<div><div>Radiotherapy is the standard treatment for nearly 60 % of cancer patients. Despite advancements such as brachytherapy, stereotactic radiotherapy, and intensity-modulated radiotherapy, further improvements in efficacy and safety are needed. Radiodynamic therapy (RDT) is gaining attention, in which improved radiotherapy outcomes are achieved with the use of porphyrins such as protoporphyrin IX, verteporfin, Mn-porphyrins, and other porphyrinoids such as phthalocyanines and texaphyrins. While the light-based excitation mechanisms of these photosensitizing agents are widely established, their radiosensitization mechanisms remain unclear and underinvestigated. A comprehensive investigation into the observed physicochemical and biological effects of these compounds during radiotherapy enables the identification of several key underlying mechanisms to explain the radiocatalytic properties of porphyrins and porphyrin-related compounds. Porphyrin-like sensitizers can (1) be excited by Cherenkov radiation, (2) be ionized by secondary electrons, (3) initiate redox cycling reactions and enhance reactive oxygen species production, and (4) interfere with critical signaling pathways. These effects may synergistically combine to enhance the effects of ionizing radiation and boost the radiosensitivity of cancer cells, offering a powerful new direction for cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117861"},"PeriodicalIF":6.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296248","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}

引用次数: 0

Discovery of hybrids of bisbibenzyl with furoxan as lysosomotropic agents for the treatment of drug-resistant non-small-cell lung cancer 双苯并与呋喃嘧啶杂交体治疗耐药非小细胞肺癌的研究

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-15 DOI: 10.1016/j.ejmech.2025.117856

Jia-Yu Sun , Si-Jie Qi , Qian Chen , Wei Guo , Xiao-Mei Zou , Gao-Qiang Zhang , Ke-Xin Liu , Hao-Yu Liu , Hong-Bo Zheng , Bin Sun , Hong-Xiang Lou

{"title":"Discovery of hybrids of bisbibenzyl with furoxan as lysosomotropic agents for the treatment of drug-resistant non-small-cell lung cancer","authors":"Jia-Yu Sun , Si-Jie Qi , Qian Chen , Wei Guo , Xiao-Mei Zou , Gao-Qiang Zhang , Ke-Xin Liu , Hao-Yu Liu , Hong-Bo Zheng , Bin Sun , Hong-Xiang Lou","doi":"10.1016/j.ejmech.2025.117856","DOIUrl":"10.1016/j.ejmech.2025.117856","url":null,"abstract":"<div><div>Twenty-one novel macrocyclic bisbibenzyl-furoxan hybrids were designed and synthesized as lysosomotropic agents, with subsequent evaluation of their anticancer potential against multidrug-resistant (A549/Taxol, MCF-7/ADR) and parental (A549, MDA-MB-231, MCF-7) cancer cell lines. Compound <strong>15a</strong> emerged as the most promising candidate, demonstrating potent antiproliferative activity against paclitaxel-resistant A549/Taxol cells (IC<sub>50</sub> = 0.87 μM) with good selectivity over normal cells. Structure-activity relationship studies established a positive correlation between p<em>K</em>a values of the hybrids and their cytotoxic potency against A549/Taxol cells. Mechanistic investigations revealed that the basic nature of <strong>15a</strong> facilitated its selective accumulation in acidic lysosomes of drug-resistant cells, where it triggered substantial nitric oxide (NO) release and reactive oxygen species (ROS) generation. This further induced lysosomal membrane permeabilization and subsequent cell apoptosis. Notably, <strong>15a</strong> displayed superior <em>in vivo</em> antitumor efficacy in A549/Taxol xenograft models compared to paclitaxel, without observable systemic toxicity. This work establishes that strategic hybridization of basic bisbibenzyl scaffolds with nitric oxide-donating furoxan moieties represents an effective lysosome-targeting approach to overcome multidrug resistance in cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117856"},"PeriodicalIF":6.0,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290007","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}

引用次数: 0

Design and synthesis of genipine derivatives for the treatment of liver fibrosis by modulating TGF-β1/Smad signaling pathway 通过调节TGF-β1/Smad信号通路治疗肝纤维化的吉尼平衍生物的设计合成

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-15 DOI: 10.1016/j.ejmech.2025.117869

Yan Cao , Jingwen Yu , Yazheng Zhu , Enyi Wu , Zhengyu Hu , Hui Miao , Qingjia Ren , Yong Yin , Caolong Li

{"title":"Design and synthesis of genipine derivatives for the treatment of liver fibrosis by modulating TGF-β1/Smad signaling pathway","authors":"Yan Cao , Jingwen Yu , Yazheng Zhu , Enyi Wu , Zhengyu Hu , Hui Miao , Qingjia Ren , Yong Yin , Caolong Li","doi":"10.1016/j.ejmech.2025.117869","DOIUrl":"10.1016/j.ejmech.2025.117869","url":null,"abstract":"<div><div>The key event in the development of liver fibrosis is that hepatic stellate cells (HSCs) actives and transforms into myofibroblasts, so inhibiting HSCs activation is an important strategy in the search for therapeutic agents for liver fibrosis. In this study, we designed and synthesized a series of novel genipin derivatives that could effectively inhibit the activation of hepatic stellate cell (HSC) line LX-2 induced by TGF-<em>β</em>1. Among them, compound <strong>C9</strong> can dose-dependently inhibit the expression of fibrosis markers (<em>α</em>-SMA and COL1A1) induced by TGF-<em>β</em>1, and has excellent <em>in vitro</em> safety. In a mouse model of CCl<sub>4</sub>-induced hepatic fibrosis, <strong>C9</strong> exhibited significant antifibrotic effects, which was significantly superior to that of genipin and without hepatotoxicity. Meanwhile, <strong>C9</strong> exhibited good pharmacokinetic properties in SD rats. Overall, compound <strong>C9</strong> is expected to be a potential candidate for the treatment of hepatic fibrosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117869"},"PeriodicalIF":6.0,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290006","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}

引用次数: 0

Targeting both wild-type EGFR and its drug-resistant mutants with erlotinib-aptamer conjugates 用厄洛替尼适体偶联物靶向野生型EGFR及其耐药突变体

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.ejmech.2025.117871

Yan Li , Jian Song , Ruixin Ge , Xiangrui Luo , Ping Zhou , Hanyue Lei , Rouhan Qian , Fan Zhang , Wei Pan , Miao Chen , Jingrui Li , Xifeng Dong , Tianliang Li , Sijin Wu , Jun Zhou , Songbo Xie

{"title":"Targeting both wild-type EGFR and its drug-resistant mutants with erlotinib-aptamer conjugates","authors":"Yan Li , Jian Song , Ruixin Ge , Xiangrui Luo , Ping Zhou , Hanyue Lei , Rouhan Qian , Fan Zhang , Wei Pan , Miao Chen , Jingrui Li , Xifeng Dong , Tianliang Li , Sijin Wu , Jun Zhou , Songbo Xie","doi":"10.1016/j.ejmech.2025.117871","DOIUrl":"10.1016/j.ejmech.2025.117871","url":null,"abstract":"<div><div>The epidermal growth factor receptor (EGFR) mutation is an actionable oncogenic driver in non-small-cell lung cancer (NSCLC). Although multiple generations of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been approved for the treatment of advanced NSCLC, acquired drug resistance after long-term administration challenges their therapeutic efficacy. In this study, using the first-generation agent erlotinib as a warhead for EGFR and an aptamer targeting insulin-like growth factor 2 receptor (IGF2R) as a recruiter for the lysosome-shuttling receptor, we develop a pan-EGFR lysosome-targeting chimera (LYTAC). A series of EGFR degraders with different linker lengths are generated, among which LY-dE#5 is the most effective degrader that directs EGFR to the lysosomal pathway for degradation. Importantly, LY-dE#5 drives not only the downregulation of the wild-type but also the mutants which include 19del, L858R/T790M, 19del/T790M/C797S, and L858R/T790M/C797S, exhibiting superior antitumor activity over Osimertinib. Further <em>in vitro</em> and <em>in vivo</em> studies demonstrate that LY-dE#5 effectively suppresses the growth of EGFR-driven cancer cells. These data indicate that the erlotinib-aptamer conjugate is an efficient pan-EGFR degrader that holds the translational potential for cancer treatment to overcome the common drug-resistance issues of EGFR-TKIs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117871"},"PeriodicalIF":6.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288280","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}

引用次数: 0

Discovery and optimization of novel tetrahydrothiazolopyridine-based pyrimidines as highly potent cyclin-dependent kinase 9 (CDK9) inhibitors 新型四氢噻唑吡啶嘧啶作为高效细胞周期蛋白依赖性激酶9 （CDK9）抑制剂的发现和优化

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.ejmech.2025.117875

Lin Chen , Zhongkai Zou , Jian Fan Cai, Wenbin Zeng, Yanting Zhang, Yimeng Liao, Peiliang Zhao

{"title":"Discovery and optimization of novel tetrahydrothiazolopyridine-based pyrimidines as highly potent cyclin-dependent kinase 9 (CDK9) inhibitors","authors":"Lin Chen , Zhongkai Zou , Jian Fan Cai, Wenbin Zeng, Yanting Zhang, Yimeng Liao, Peiliang Zhao","doi":"10.1016/j.ejmech.2025.117875","DOIUrl":"10.1016/j.ejmech.2025.117875","url":null,"abstract":"<div><div>Cyclin-dependent kinase 9 (CDK9) is a well-validated target for cancer treatment. In this work, starting from a multitargeted CDK1/2/9 inhibitor ZK304709, optimization efforts successfully led to the discovery of a highly potent selective CDK9 inhibitor <strong>8e</strong> which exhibites significant enzyme inhibitory activity (IC<sub>50</sub> = 5.5 nM) which is comparable to that of ZK304709 (IC<sub>50</sub> = 5.0 nM). More importantly, <strong>8e</strong> shows high selectivity for CDK9 versus CDK1, CDK2, CDK4, and CDK6, respectively. Additionally, <strong>8e</strong> possesses greater or similar antiproliferative efficacy with ZK304709 against HeLa, A549, HCT116, and MCF-7 cells, and exhibits potent <em>in vivo</em> antitumor activity in HCT116 xenograft mouse models with tumor growth inhibition of 59.2 % at 60 mg/kg without obvious signs of toxicity. Research on the mechanism reveals that <strong>8e</strong> could concentration-dependently cause the G<sub>2</sub>/M phase arrest and induce cell apoptosis in HCT116 cells. These observations provide a novel tetrahydrothiazolopyridine-based pyrimidine scaffold to further develop selective CDK9 inhibitors for cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117875"},"PeriodicalIF":6.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290008","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}

引用次数: 0

Dismantling the epigenetic alliance: Emerging strategies to disrupt the PRMT5:MEP50 complex for cancer therapy 拆除表观遗传联盟：破坏PRMT5:MEP50复合体用于癌症治疗的新策略

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-14 DOI: 10.1016/j.ejmech.2025.117870

Faris F. Aba Alkhayl

{"title":"Dismantling the epigenetic alliance: Emerging strategies to disrupt the PRMT5:MEP50 complex for cancer therapy","authors":"Faris F. Aba Alkhayl","doi":"10.1016/j.ejmech.2025.117870","DOIUrl":"10.1016/j.ejmech.2025.117870","url":null,"abstract":"<div><div>The protein arginine methyltransferase 5 (PRMT5) and its obligate cofactor MEP50 (WDR77) form a highly conserved enzymatic complex that orchestrates key epigenetic processes, including histone arginine methylation, transcriptional repression, RNA splicing, and DNA damage repair. Dysregulation of the PRMT5:MEP50 complex has been implicated in the initiation and progression of diverse cancers, where it contributes to silencing of tumor suppressor genes, enhancement of oncogenic signaling, and maintenance of stem-like phenotypes. While most therapeutic strategies have focused on catalytic inhibition of PRMT5 via S-adenosylmethionine-competitive compounds, recent insights into the structural biology of PRMT5:MEP50 have revealed the protein–protein interaction (PPI) interface as a novel and selective therapeutic target. This review provides a comprehensive analysis of the structural basis and biological significance of the PRMT5:MEP50 interaction, highlighting its role in tumorigenesis and its functional specificity across cancer types. We examine emerging therapeutic strategies aimed at disrupting this interface, including rationally designed small-molecule inhibitors and natural compounds like Sulforaphane (SFN), which selectively impair PRMT5:MEP50 function without affecting global methylation. Moreover, we explore cancer models—such as prostate cancer, mesothelioma, T-cell leukemia, and lung cancer—that exhibit dependency on PRMT5:MEP50, and discuss their response to genetic and pharmacological disruption of the complex. Finally, we outline key challenges and future directions in translating PRMT5:MEP50 PPI inhibitors into clinical settings, emphasizing the importance of biomarker-guided patient selection, combination therapy strategies, and optimization of drug pharmacokinetics. Together, these insights underscore the therapeutic promise of targeting the PRMT5:MEP50 interaction as a next-generation approach to precision epigenetic cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117870"},"PeriodicalIF":6.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288279","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}

引用次数: 0

Discovery of pyrrolo[2,3-d]pyrimidine derivatives as novel FLT3/IRAK4 inhibitors 吡咯[2,3-d]嘧啶衍生物作为新型FLT3/IRAK4抑制剂的发现

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-13 DOI: 10.1016/j.ejmech.2025.117845

Haibin Yuan , Yue Gao , Peipei Wang , Xiaowu Dong , Jia Li , Chenxi Wang , Jinxin Che , Yubo Zhou , Tao Liu

{"title":"Discovery of pyrrolo[2,3-d]pyrimidine derivatives as novel FLT3/IRAK4 inhibitors","authors":"Haibin Yuan , Yue Gao , Peipei Wang , Xiaowu Dong , Jia Li , Chenxi Wang , Jinxin Che , Yubo Zhou , Tao Liu","doi":"10.1016/j.ejmech.2025.117845","DOIUrl":"10.1016/j.ejmech.2025.117845","url":null,"abstract":"<div><div>Starting with the lead compound <strong>L-1</strong>, a series of pyrrolo[2,3-d]pyrimidine derivatives were developed as FLT3/IRAK4 inhibitors through three rounds of rational structural optimization. Among them, <strong>HB-29</strong> had the remarkable activity towards FLT3-WT (IC<sub>50</sub> = 1.95 nM) and IRAK4 (IC<sub>50</sub> = 53.72 nM), outperforming the positive control, CA-4948. Besides, it exhibited excellent activities in MV4-11, MOLM3, and BaF3 cells with varying FLT3-TKD and FLT3-ITD-TKD mutations, highlighting its potential to overcome acquired resistance. The toxicity of <strong>HB-29</strong> to normal bone marrow cell line HS-5 is relatively low (SI > 2000). Mechanistic studies revealed that <strong>HB-29</strong> inhibited FLT3 and IRAK4 pathways in a dose-dependent manner, promoting cell apoptosis. Notably, in the cytokine-induced cell model, <strong>HB-29</strong> efficiently induced apoptosis, and while also enhancing SOD activity and reducing ROS accumulation, thereby demonstrating its potential to overcome adaptive resistance. Moreover, <strong>HB-29</strong> demonstrated an acceptable bioavailability (F = 13.4 %). These findings confirm that FLT3/IRAK4 inhibitor is a promising strategy for the treatment of AML.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117845"},"PeriodicalIF":6.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278790","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}

引用次数: 0

Rational design of CZL-S092: A novel indazole-based PLK4 inhibitor targeting neuroblastoma through virtual screening and fragment-based drug design strategies 通过虚拟筛选和基于片段的药物设计策略，合理设计基于茚唑的靶向神经母细胞瘤PLK4抑制剂CZL-S092

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-06-13 DOI: 10.1016/j.ejmech.2025.117867

Nian liu , Ningyuan Hu , Cunzheng Fan , Minghui Tong , Xuan Shi , Han Wang , Pengkun Sun , Shuyi Mu , Zehui Qi , Wenqiang Sun , Haoyu Zhang , Yixiang Sun , Zixuan Gao , Dongmei Zhao , Maosheng Cheng

{"title":"Rational design of CZL-S092: A novel indazole-based PLK4 inhibitor targeting neuroblastoma through virtual screening and fragment-based drug design strategies","authors":"Nian liu , Ningyuan Hu , Cunzheng Fan , Minghui Tong , Xuan Shi , Han Wang , Pengkun Sun , Shuyi Mu , Zehui Qi , Wenqiang Sun , Haoyu Zhang , Yixiang Sun , Zixuan Gao , Dongmei Zhao , Maosheng Cheng","doi":"10.1016/j.ejmech.2025.117867","DOIUrl":"10.1016/j.ejmech.2025.117867","url":null,"abstract":"<div><div>Polo like kinase 4 (PLK4) is a critical member of the polo-like kinase family that works as a master regulator of centriole duplication and mitotic progression. Overexpression of PLK4 has been documented in various cancers and PLK4 inhibitors are regarded as a potential strategy for cancer treatment. In this study, we identified indazole derivative <strong>8</strong> as a hit compound through a virtual screening approach. Subsequent fragment-based rational drug design strategy was used to modify the chemical structure of compound <strong>8</strong> and yielded 34 indazole derivatives targeting PLK4. Among them, compound <strong>34b</strong> (<strong>CZL-S092</strong>) exhibited a potent PLK4 inhibitory activity with an IC<sub>50</sub> value of 0.9 nM, and exceptional selectivity in a panel of 37 kinases. At the cellular level, compound <strong>34b</strong> demonstrated significant antiproliferative activity against the neuroblastoma cell lines IMR-32 and SH-SY5Y with IC<sub>50</sub> values of 1.143 μM and 1.329 μM, respectively. Moreover, the colony formation, flow cytometry, wound healing and immunofluorescence analysis further confirmed the <em>in vitro</em> antitumor effects of compound <strong>34b</strong>. Meanwhile, compound <strong>34b</strong> displayed excellent <em>in vitro</em> drug permeability and plasma protein binding. Furthermore, compound <strong>34b</strong> exhibited acceptable <em>in vivo</em> pharmacokinetic properties with the oral bioavailability of 22.1 %. Overall, compound <strong>34b</strong> exhibited potent anti-neuroblastoma activities and acceptable pharmacokinetic properties, which served as a favorable lead compound targeting PLK4.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117867"},"PeriodicalIF":6.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288281","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}

引用次数: 0