European Journal of Medicinal Chemistry最新文献_第2页

Rational design of dual PB2/JAK2 inhibitors achieving balanced antiviral and host-directed immunomodulatory effects 双重PB2/JAK2抑制剂的合理设计，实现平衡的抗病毒和宿主定向免疫调节作用

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-06 DOI: 10.1016/j.ejmech.2026.118642

Yujian Yang , Binhao Rong , Huanyu Shi , Kunyu Lu , Xinxin Lin , Yuanmei Wen , Xingyu Zhou , Peisen Zheng , Xinshan Deng , Xumu Zhang , Shuwen Liu , Qifan Zhou

{"title":"Rational design of dual PB2/JAK2 inhibitors achieving balanced antiviral and host-directed immunomodulatory effects","authors":"Yujian Yang , Binhao Rong , Huanyu Shi , Kunyu Lu , Xinxin Lin , Yuanmei Wen , Xingyu Zhou , Peisen Zheng , Xinshan Deng , Xumu Zhang , Shuwen Liu , Qifan Zhou","doi":"10.1016/j.ejmech.2026.118642","DOIUrl":"10.1016/j.ejmech.2026.118642","url":null,"abstract":"<div><div>Infection with the influenza virus provokes an excessive immune reaction, triggering a cytokine storm that can cause severe inflammation and lead to conditions such as pneumonia and myocarditis. Herein, we propose a dual-target strategy that simultaneously targets the viral PB2 protein and the host JAK2 kinase, aiming to not only eliminate the virus but also modulate the immune response, facilitating rapid recovery of the body's health. In this article, the design and discovery of novel PB2/JAK2 dual-target inhibitors are reported. Through rational design and structure-guided optimization, we identified compound <strong>4B</strong>, which exhibited potent anti-H1N1 activity (MDCK cell EC<sub>50</sub> = 15 nM) and JAK2 inhibitory activity (JAK2 IC<sub>50</sub> = 49 nM). <strong>Notably, 4B demonstrated favorable pharmacokinetic properties in mice, achieving excellent oral bioavailability (F = 99.4%).</strong> Furthermore, our findings show that compound <strong>4B</strong> significantly downregulates NP and PB2 protein expression. Concurrently, <strong>4B</strong> also inhibits the mRNA expression of key pro-inflammatory cytokines (IL-6, TNF-α, IFN-β) in both inflammatory and influenza-infected models. This study demonstrates the promising potential of dual inhibition, targeting both viral replication and the host inflammatory response, for the development of anti-influenza therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118642"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135341","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

Structural optimization of natural product honokiol to discover novel membrane-targeting antibacterial agents against Gram-positive bacteria 天然产物本木酚的结构优化，以发现新的膜靶向抗革兰氏阳性细菌的抗菌剂

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-10 DOI: 10.1016/j.ejmech.2026.118674

Ninan Dai , Yiyu Wang , Yong Yang , Yuting Zhang , Huan Ge , Farhad Ghazali , Bao Fu , Yinhu Wang , Song Qin

{"title":"Structural optimization of natural product honokiol to discover novel membrane-targeting antibacterial agents against Gram-positive bacteria","authors":"Ninan Dai , Yiyu Wang , Yong Yang , Yuting Zhang , Huan Ge , Farhad Ghazali , Bao Fu , Yinhu Wang , Song Qin","doi":"10.1016/j.ejmech.2026.118674","DOIUrl":"10.1016/j.ejmech.2026.118674","url":null,"abstract":"<div><div>The global increase in infections caused by multidrug-resistant bacteria, coupled with a dwindling antibiotic pipeline, underscores an urgent need for new therapeutic agents. Inspired by the design principles of cationic antimicrobial peptides, we developed a new class of honokiol-based amphiphiles. From this series, compound <strong>20C</strong> emerged as a promising lead, demonstrating potent <em>in vitro</em> activity against Gram-positive bacteria (MICs = 0.5-2 μg/mL). It exhibited a favorable safety profile characterized by low hemolytic (HC<sub>50</sub> = 771.8 μg/mL) and cytotoxic activity (CC<sub>50</sub> = 28.03 μg/mL), along with good plasma stability. <strong>20C</strong> also displayed rapid bactericidal kinetics, a low resistance frequency, and efficacy in inhibiting biofilm formation and disrupting mature biofilms. A detailed mechanistic investigation established that <strong>20C</strong> exerted its effect by dissipation of membrane potential, increasing permeability, thereby disrupting membrane integrity. This primary membrane damage triggered secondary lethal events, including ROS accumulation and leakage of proteins and DNA. Notably, <strong>20C</strong> displayed superior efficacy compared to vancomycin in an <em>in vivo</em> infection model. These findings established <strong>20C</strong> as a promising candidate and underscore the potential of this amphiphilic design strategy in antibiotic discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118674"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153255","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

Development of the first-in-class RNF4 PROTAC degrader as potential therapeutics for hepatocellular carcinoma RNF4 PROTAC降解剂作为肝细胞癌潜在治疗药物的研究进展

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-10 DOI: 10.1016/j.ejmech.2026.118668

Hui Wan , Yihang Liu , Huimin Chang , Kai Zhang , Zhenzhen Li , Haisen Ni , Jie Xu , Bo Pan , Kongkai Zhu , Junchi Hu , Shuai Wang , Dongqin Yang , Xiaobo Wang , Yongjun Dang , Sanyong Zhu

{"title":"Development of the first-in-class RNF4 PROTAC degrader as potential therapeutics for hepatocellular carcinoma","authors":"Hui Wan , Yihang Liu , Huimin Chang , Kai Zhang , Zhenzhen Li , Haisen Ni , Jie Xu , Bo Pan , Kongkai Zhu , Junchi Hu , Shuai Wang , Dongqin Yang , Xiaobo Wang , Yongjun Dang , Sanyong Zhu","doi":"10.1016/j.ejmech.2026.118668","DOIUrl":"10.1016/j.ejmech.2026.118668","url":null,"abstract":"<div><div>Ring Finger Protein 4 (RNF4) recognizes poly-SUMOylated proteins via its SUMO-Interacting Motifs (SIMs) and subsequently ubiquitinates them, thus effecting some key regulatory proteins involved in cancer development and progression. Our previous study found RNF4 was a potential target for HCC interruption. However, none of its inhibitor has been developed so far. Targeting RNF4 for degradation, rather than mere binding, emerged as a promising alternative strategy. To this end, we designed, synthesized and evaluated 28 PROTACs targeting RNF4 based on a reported covalent binder. Among them, <strong>RD12</strong> was identified as the lead compound through a systematic screening. <strong>RD12</strong> showed efficient RNF4 degradation activity as well as potent anti-proliferative activity in multiple HCC cell lines. Notably, it exhibited significant anti-tumour activity in a HCC mouse model without noticeable side effects. Mechanistic studies confirmed <strong>RD12</strong> degraded RNF4 via the ubiquitin-proteasome system, and it induced DNA damage and apoptosis. These findings collectively underscore <strong>RD12</strong> as the first pioneering RNF4 degrader and indicate its potential for HCC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118668"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153097","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 novel structural imidazolylvinylquinolones exerting excellent broad-spectrum antibacterial efficacy with multitargeting potential 新型结构咪唑基乙烯基喹诺酮类药物的发现，具有良好的广谱抗菌作用和多靶点潜力

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-02 DOI: 10.1016/j.ejmech.2026.118643

Yi-Min Tan , Aisha Bibi , Jin-Ping Chen , Wei-Wei Gao , Yu Cheng , Cheng-He Zhou

{"title":"Discovery of novel structural imidazolylvinylquinolones exerting excellent broad-spectrum antibacterial efficacy with multitargeting potential","authors":"Yi-Min Tan , Aisha Bibi , Jin-Ping Chen , Wei-Wei Gao , Yu Cheng , Cheng-He Zhou","doi":"10.1016/j.ejmech.2026.118643","DOIUrl":"10.1016/j.ejmech.2026.118643","url":null,"abstract":"<div><div>A unique type of imidazolylvinylquinolones (IVQs) as novel structural scaffold were developed which afforded excellent broad-spectrum antibacterial efficacy with multitargeting potential. Most of the prepared IVQs gave high antibacterial activity and broad antibacterial spectrum, and especially ethyl IVQ <strong>14a</strong>, in which the ethyl group was the most suitable fragment among all the investigated substituents to perform the most effective biosupramolecular effect, showed potent antibacterial activity against MRSA (MIC = 0.25 μg/mL), with an enhanced efficacy 16-fold that of ciprofloxacin. Molecule <strong>14a</strong> also demonstrated low drug resistance, hemolysis, and cytotoxicity, and rapidly bactericidal ability. Mechanism evaluation revealed that molecule <strong>14a</strong> could not only interfere with membranous function and form DNA-<strong>14a</strong> supramolecular complex by intercalation that might obstruct DNA replication, but also effectively interact with lactate dehydrogenase <em>via</em> hydrogen bonds which could obstruct the function of enzyme and inhibit bacterial metabolism, thereby exerting potent bactericidal effect. These potential multitargeting antibacterial actions enabled ethyl IVQ <strong>14a</strong> to exhibit stronger anti-MRSA efficacy without the obvious development of bacterial resistance than ciprofloxacin <em>in vivo</em>. This series of medicinal chemobiological evaluation towards the topic compounds strongly suggested the development potential of unique imidazolylvinylquinolones as novel structural scaffold to combat bacterial resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118643"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109851","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 KRAS-G12D degraders via exploration of various E3 ligases 通过探索各种E3连接酶发现KRAS-G12D降解物

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-03 DOI: 10.1016/j.ejmech.2026.118635

Hyerin Yim , Xiangyang Song , Yue Zhong, Jacqueline Hu, Yan Xiong, Jian Jin

{"title":"Discovery of KRAS-G12D degraders via exploration of various E3 ligases","authors":"Hyerin Yim , Xiangyang Song , Yue Zhong, Jacqueline Hu, Yan Xiong, Jian Jin","doi":"10.1016/j.ejmech.2026.118635","DOIUrl":"10.1016/j.ejmech.2026.118635","url":null,"abstract":"<div><div>PROteolysis TArgeting Chimera (PROTAC) is a promising modality for targeted protein degradation. Although 600+ E3 ligases exist in the human genome, most PROTACs exploit a very limited set of E3 ligases, primarily CRBN and VHL. In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133. Through this structure–activity relationship (SAR) study, we discovered two potent degraders: <strong>30</strong> (CRBN-based) and <strong>41</strong> (VHL-based), both of which effectively degraded KRAS-G12D and suppressed downstream signaling. By introducing a triazole-based VHL ligand, we subsequently discovered <strong>43</strong>, which showed improved degradation and antiproliferative activity comparable to a previously reported KRAS-G12D degrader. In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 ligase compatibility. These findings highlight the importance of E3 ligase selection in the development of effective KRAS-G12D degraders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118635"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109847","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

Identification of a new protein-RNA interaction inhibitor targeting the KH34 region of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2/IMP2) 靶向胰岛素样生长因子2 mRNA结合蛋白2 (IGF2BP2/IMP2) KH34区蛋白- rna相互作用抑制剂的鉴定

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-04 DOI: 10.1016/j.ejmech.2026.118624

Aylin Berwanger , Konrad Wagner , Simon Both , Andreas M. Kany , Kyana Mazlom , Anna K.H. Hirsch , Alexandra K. Kiemer , Martin Empting

{"title":"Identification of a new protein-RNA interaction inhibitor targeting the KH34 region of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2/IMP2)","authors":"Aylin Berwanger , Konrad Wagner , Simon Both , Andreas M. Kany , Kyana Mazlom , Anna K.H. Hirsch , Alexandra K. Kiemer , Martin Empting","doi":"10.1016/j.ejmech.2026.118624","DOIUrl":"10.1016/j.ejmech.2026.118624","url":null,"abstract":"<div><div>Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2/IMP2) plays a crucial role in the posttranscriptional regulation of gene expression and influences various cellular processes including cell growth, differentiation, and metabolism. Dysregulation of IMP2 has been associated with several diseases, including cancer and metabolic disorders. Targeting IMP2 with small molecules is a promising therapeutic strategy. However, the structural diversity of IMP2-targeting compounds remains limited. In this study, we present a comprehensive screening approach with the aim of identifying new structural classes of compounds that can inhibit IMP2 activity, particularly its binding to the KH34 domain. Screening of a chemically diverse library comprising 10,240 compounds using fluorescence polarization–based assays led to the identification of ten primary actives belonging to five distinct structural classes. After rigorous resynthesis and hit validation, only one compound comprising a sulfonamide scaffold reproducibly inhibited the KH34–RNA interaction <em>in vitro</em>. This hit was further characterized by STD-NMR and <em>in vitro</em> ADME profiling, including solubility, lipophilicity, metabolic stability, plasma protein binding, and cellular permeability. While this sulfonamide-based inhibitor exhibits clear biochemical activity and a defined binding mode at the KH34 RNA-binding interface, its limited cellular permeability and high plasma protein binding currently preclude cellular efficacy. This work identifies a new structural class of IMP2 KH34 inhibitors serving as a starting point for an ongoing hit-to-lead optimization campaign towards next-generation anti-cancer drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118624"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135335","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

Structure-activity relationship of steroidal-nitroxide hybrids: Dual-modulators of glucocorticoid receptor signalling and cellular redox state 甾体-氮氧化物杂交种的构效关系：糖皮质激素受体信号和细胞氧化还原状态的双重调节剂

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-07 DOI: 10.1016/j.ejmech.2026.118655

Carl P. Soltau , Ban Qi Tay , Alexander P. Martyn , Derek J. Richard , Mark N. Adams , Steven E. Bottle

{"title":"Structure-activity relationship of steroidal-nitroxide hybrids: Dual-modulators of glucocorticoid receptor signalling and cellular redox state","authors":"Carl P. Soltau , Ban Qi Tay , Alexander P. Martyn , Derek J. Richard , Mark N. Adams , Steven E. Bottle","doi":"10.1016/j.ejmech.2026.118655","DOIUrl":"10.1016/j.ejmech.2026.118655","url":null,"abstract":"<div><div>Inflammation and redox imbalance are hallmarks of many diseases. Here, we report the synthesis and systematic evaluation of steroid-nitroxide hybrid compounds as dual-acting anti-inflammatory and redox-modulating agents. Hybrids were generated <em>via</em> ester (<strong>1a-c</strong>, <strong>2a-b</strong>), amide (<strong>1d-h</strong>), and ether (<strong>3a-c</strong>) linkages at the C21 position of corticosteroids prednisolone, cortisol, and dexamethasone. The hybrids exhibit glucocorticoid receptor (GR) activity and suppress IL-6 secretion <em>in vitro</em> at variable potencies, some comparable to commercial corticosteroids. Cellular metabolic evaluation demonstrates various rates of intracellular cleavage for ester- and amide-linked hybrids, while ether-linked hybrids remain intact. Assessment of general reactive oxygen species (ROS) levels <em>via</em> the fluorogenic probe 2′,7′-dichlorofluorescein diacetate (DCFDA) demonstrated linker-dependent pro-oxidative effects, with poorly labile and non-cleavable compounds (<strong>1a</strong>, <strong>3a-c</strong>) causing sustained ROS elevation, while cleavable hybrids produced only transient, recoverable increases. Notably, one hybrid (<strong>1a</strong>) demonstrated higher ROS elevation in A549 cells over normal human fibroblasts (i.e. NFF cells) suggesting certain structural features of this hybrid induce specificity. Live-cell imaging using fluorescent analogues supports the mechanism of intracellular cleavage and efflux for cleavable hybrids, while non-cleavable hybrids remain within the cell. These findings demonstrate that steroidal-nitroxide hybrids harness both anti-inflammatory and redox modulation pathways, positioning them as a novel treatment strategy where dual anti-inflammatory and pro-oxidant strategies are advantageous.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118655"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138918","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

Semi-rigid linkers improve the pharmacokinetic properties and therapeutic efficacy of BET PROTACs for cancer therapy 半刚性连接体改善BET protac在癌症治疗中的药动学特性和疗效

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-03 DOI: 10.1016/j.ejmech.2026.118644

Su Yu , Shichuan Hu , Weilin Wang , Chuntao Pan , Hongjia Zhang , Cong Zhou , Yang Liu , Rui Li

{"title":"Semi-rigid linkers improve the pharmacokinetic properties and therapeutic efficacy of BET PROTACs for cancer therapy","authors":"Su Yu , Shichuan Hu , Weilin Wang , Chuntao Pan , Hongjia Zhang , Cong Zhou , Yang Liu , Rui Li","doi":"10.1016/j.ejmech.2026.118644","DOIUrl":"10.1016/j.ejmech.2026.118644","url":null,"abstract":"<div><div>PROTACs offer a novel therapeutic strategy for addressing diseases driven by aberrant expression of pathogenic proteins. In this study, we identified a series of PROTAC molecules capable of degrading BRD2, BRD3, and BRD4. Structure–activity relationship analysis led to the discovery of <strong>CR10</strong>, a highly potent degrader that exhibited remarkable activity in MV4-11 cells. Mechanistic studies demonstrated that <strong>CR10</strong> induced sustained degradation of target proteins <em>via</em> the ubiquitin–proteasome system. In mice models, intraperitoneal administration at 20 mg/kg achieved an exceptional bioavailability of 108.27%. Furthermore, <strong>CR10</strong> significantly inhibited the growth of MV4-11 and A549 xenograft tumors at a dose as low as 2 mg/kg, without apparent toxicity. This semi-rigid linker–containing degrader represented a promising new mechanism-based candidate for the treatment of hematologic malignancies and lung cancer, warranting further investigation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118644"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109848","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, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy 新型吡咯[1,2-b]吡啶嗪-2(1H)-ones作为PARP1肿瘤选择性抑制剂的设计、合成及生物学评价

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-04 DOI: 10.1016/j.ejmech.2026.118650

Qiaolin He , Jing He , Xiajuan Huan , Shanshan Song , Xiaofei Zhang , Qian He , Zehong Miao , Jinxue He , Chunhao Yang

{"title":"Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy","authors":"Qiaolin He , Jing He , Xiajuan Huan , Shanshan Song , Xiaofei Zhang , Qian He , Zehong Miao , Jinxue He , Chunhao Yang","doi":"10.1016/j.ejmech.2026.118650","DOIUrl":"10.1016/j.ejmech.2026.118650","url":null,"abstract":"<div><div>Poly-ADP-ribose-polymerase inhibitors (PARPi) hold significant clinical value in the treatment of BRCA-deficient tumors, but their substantial hematological toxicity limits a broader scope of clinical applications. Studies suggest that the toxicity may be associated with selective deficiency between PARP1 and PARP2. In this study, we designed and synthesized a series of inhibitors containing novel pyrrolo[1,2-<em>b</em>]pyridazin-2(1<em>H</em>)-one scaffold selectively targeting PARP1. Among these compounds, <strong>YCH3971</strong> exhibited potent inhibiting activity against PARP1 with an IC<sub>50</sub> of 7.52 nM, showing a remarkable subtype selectivity compared with PARP2 (>1000-fold). Also, <strong>YCH3971</strong> possessed a strong antiproliferative activity on BRCA mutant MDA-MB-436 cells with an IC<sub>50</sub> of 2.10 nM. However, since the oral bioavailability of <strong>YCH3971</strong> in rats is only 1.2%, we have not yet initiated in vivo efficacy studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118650"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122320","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 Menin-MLL inhibitors targeting acute myeloid leukemia 靶向急性髓系白血病的Menin-MLL抑制剂的发现和优化。

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-04-05 Epub Date: 2026-02-05 DOI: 10.1016/j.ejmech.2026.118641

Qitao Xiao , Yuxian Wang , Zheyuan Shen , Jun Mo , Cong Li , Rongkuan Jiang , Jingyu Zhang , Yubo Zhou , Xiaowu Dong , Hanlin Wang , Tao Liu

{"title":"Discovery and optimization of Menin-MLL inhibitors targeting acute myeloid leukemia","authors":"Qitao Xiao , Yuxian Wang , Zheyuan Shen , Jun Mo , Cong Li , Rongkuan Jiang , Jingyu Zhang , Yubo Zhou , Xiaowu Dong , Hanlin Wang , Tao Liu","doi":"10.1016/j.ejmech.2026.118641","DOIUrl":"10.1016/j.ejmech.2026.118641","url":null,"abstract":"<div><div>A machine learning-guided strategy, which integrated unsupervised structural clustering to identify diverse scaffolds for molecular hybridization followed by synergistic QSAR and molecular docking screening, identified lead compound 7. Guided by this lead, a series of thieno[2,3-<em>d</em>]pyrimidine derivatives were developed as menin inhibitors through several rounds of rational structural optimization. Among them, compound <strong>A13</strong> exhibited potent anti-proliferative activity against MV4-11 cells (0.379 ± 0.182 μM). Besides, mechanistic studies confirmed <strong>A13</strong> disrupts menin-MLL interactions, induces cell differentiation, and selectively inhibits MLL-rearranged (MV4-11, MOLM-13) and DNMT3A/NPM1-mutated (OCI-AML3) leukemia cells. The stable binding mode of A13 with menin was further elucidated by molecular dynamics simulations. Moreover, <strong>A13</strong> exhibited favorable oral pharmacokinetic properties, characterized by rapid absorption (T<sub>max</sub> = 1.67 h) and high plasma exposure (AUC<sub>0–t</sub> = 2241 ng h/mL), demonstrating its potential as a promising candidate for further preclinical development against MLL-rearranged AML.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118641"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135340","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