European Journal of Medicinal Chemistry最新文献

{"title":"Approaching Gallium-68 radiopharmaceuticals for tumor diagnosis: a Medicinal Chemist’s perspective","authors":"Francesca Musumeci, Alessandro Fasce, Marta Falesiedi, Federica Oleari, Giancarlo Grossi, Anna Carbone, Silvia Schenone","doi":"10.1016/j.ejmech.2025.117760","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117760","url":null,"abstract":"Nuclear medicine has revolutionized disease diagnosis and treatment, particularly in oncology, by enabling precise imaging and targeted therapies using radiopharmaceuticals. Recently, Gallium-68 (⁶⁸Ga) has emerged as a powerful positron emission tomography (PET) imaging agent, with a growing role in theranostics when paired with ¹⁷⁷Lu for cancer treatment. The ability to obtain ⁶⁸Ga from ⁶⁸Ge/⁶⁸Ga generators, along with its favorable radiochemical and pharmacokinetic properties, has driven an increasing number of clinical applications, which culminated with the approvals of ⁶⁸Ga-DOTA-TOC and ⁶⁸Ga-DOTA-TATE for the treatment of neuroendocrine tumors, and ⁶⁸Ga-PSMA-11 for prostate cancer over the past decade. This review provides a comprehensive overview of ⁶⁸Ga radiochemistry, chelators, and key compounds in clinical trials, highlighting the potential of this radionuclide in precision oncology.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980205","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 N-(3-fluorophenyl)-2-(4-((7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)amino)phenyl)acetamide as the first orally active selective Aurora Kinase B Inhibitor","authors":"Phuc Tran, Marialuisa Moccia, Xiuqi Wang, Annalisa Brescia, Giorgia Federico, Naresh Gunaganti, Zhengyu Wang, Min Yang, Minmin Wang, Baha’a Jabali, Wei Yan, Brendan Frett, Massimo Santoro, Francesca Carlomagno, Hong-yu Li","doi":"10.1016/j.ejmech.2025.117735","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117735","url":null,"abstract":"Cell cycle deregulation is a crucial hallmark of tumorigenesis, leading to uncontrolled cell growth. Overexpression of serine/threonine aurora kinase B (AURKB) is a common feature of human cancer, particularly of the most aggressive subtypes, and it contributes to the alteration of the cell cycle. Thus, AURKB is considered a promising target for cancer treatment; however, no AURKB pharmacological inhibitor has been approved so far. We previously reported <strong>SP-96</strong>, a quinazoline non-ATP competitive AURKB inhibitor, which exhibited sub nanomolar activity in enzymatic assay. However, <strong>SP-96</strong> cellular activity was hampered by its poor cellular activities. Herein, we designed and synthesized a new series of quinazoline derivatives featuring improved membrane penetration. Compound <strong>4b</strong> demonstrated efficacy in human cancer-derived cells and was orally active at low dose in a mouse xenograft model and correlated with the drug concentration in plasma. Importantly, a closely related compound <strong>7o</strong> attached with solubilizing group is orally bioavailable in rats. In conclusion, compounds <strong>4b</strong> and <strong>7o</strong> represents a promising lead series for further optimization to develop an oral clinical AURKB inhibitor candidate.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940419","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":"Structure-directing optimization of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzamide derivatives as selective receptor tyrosine kinase-like orphan receptor 1 (ROR1) inhibitors for cancer therapy","authors":"Qingquan Zheng, Hulin Ma, Dongdong Luo, Xingyang Qiu, Yue Ming, Wenchen Pu, Min Ai, Jianhua He, Yong Peng","doi":"10.1016/j.ejmech.2025.117755","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117755","url":null,"abstract":"Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an attractive therapeutic target for various cancers, including leukemia and lung cancer. Although some biological agents have entered clinical trials and several small-molecule inhibitors have been developed, selective ROR1 inhibitors remain underexplored. In our previous studies, we identified <strong>LDR102,</strong> an indole derivative, as a ROR1 inhibitor with favorable binding affinity and potent antitumor efficacy. However, <strong>LDR102</strong> exhibited moderate ROR1 inhibitory activity and “off-target” effects on other kinases, such as c-Kit and Abl^T315I, limiting its further development. To address these limitations, we optimized <strong>LDR102</strong> and synthesized a series of <em>N</em>-(2,3-dihydrobenzo[<em>b</em>][1,4]dioxin-6-yl)benzamide derivatives as selective ROR1 inhibitors, culminating in the identification of compound <strong>9i</strong>, which possesses favorable ROR1 inhibitory activity, good selectivity, and potent anti-tumor activity <em>in vivo</em> and <em>in vitro</em>.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"116 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946005","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":"Design, Synthesis, and Biological Evaluation of TRPV4-KCa2.3 Coupling Enhancers as Novel Therapeutic Agents for Hypertension","authors":"Shaying Yang, Dongyu Wang, Huabing Wang, Junlan Shao, Chunlei Tang","doi":"10.1016/j.ejmech.2025.117724","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117724","url":null,"abstract":"Although current treatment strategies for hypertension are well-developed, there remains a group of patients who do not respond adequately to available medications. As a result, the identification of new therapeutic targets and the design of target-specific drugs are crucial directions for the future management of hypertension. Our previous research identified the TRPV4-KCa2.3 complex as a novel target for hypertension treatment, leading to the discovery of the positive compound JNc-440. Using JNc-440 as a lead molecule, 21 compounds were designed and synthesized across five distinct series. Among these, representative compounds <strong>IB-2</strong> and <strong>II-9</strong> demonstrated the ability to restore the coupling of the decoupled complex under hypertensive conditions and significantly reduced blood pressure in a high salt-induced hypertensive mouse model. This work lays a foundation for the future development of novel therapeutics targeting hypertension.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946004","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 indole derivatives as STING degraders","authors":"Yuxiang An, Yan Zhang, Xin Luo, Yaohan Lan, Meiyu Geng, Wenhu Duan, Zuoquan Xie, Hefeng Zhang","doi":"10.1016/j.ejmech.2025.117747","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117747","url":null,"abstract":"Aberrant activation of the stimulator of interferon genes (STING) pathway is associated with the development of various inflammatory and autoimmune diseases. Targeting STING for degradation represents a novel strategy for the treatment of these diseases. In this study, we designed and synthesized a series of STING-PROTACs based on a nitro-free covalent warhead and different E3 ligase binders. The representative compound <strong>2h</strong> specifically degraded STING protein through the proteasome pathway with a DC₅₀ value of 3.23 μM and exhibited sustained degradation activity over 72 h. Further biological studies demonstrated that compound <strong>2h</strong> inhibited STING signaling and effectively suppressed immune-inflammatory cytokines both <em>in vitro</em> and <em>in vivo</em>. Moreover, compound <strong>2h</strong> offered better safety compared to its warhead molecule and SP23. Collectively, compound <strong>2h</strong> is a potent nitro-free covalent STING degrader and warrants further investigation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940036","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":"Targeting KRASG12C Mutation: Development of effective strategies to overcome drug resistance and limited efficacy","authors":"Rui Li ,&nbsp;Xu Huang ,&nbsp;Rui Wang ,&nbsp;Zhenhua Ren ,&nbsp;Yong Zhu ,&nbsp;Tao Lu ,&nbsp;Yan Sun ,&nbsp;Hao Cui","doi":"10.1016/j.ejmech.2025.117718","DOIUrl":"10.1016/j.ejmech.2025.117718","url":null,"abstract":"<div><div>The KRAS^G12C mutation causes the KRAS protein to remain in a constantly activated state, thereby promoting cell proliferation and cancer progression. As researchers have transitioned the KRAS^G12C mutation from being “undruggable\" to “druggable\", the development of KRAS^G12C inhibitors has reached a peak. However, some KRAS^G12C inhibitors have shown resistance in preclinical studies and clinical trials, resulting in poor clinical outcomes and limiting their application. This review summarizes emerging strategies to overcome resistance, including optimization strategies for KRAS^G12C mutation site inhibitors (including covalent inhibitors and degraders), as well as potential therapeutic strategies involving combination therapies and multi-target inhibition targeting major resistance mechanisms. Additionally, it discusses the potential issues and challenges that may arise in the development of treatments for KRAS^G12C mutation resistance. It is hoped that this review can provide insightful perspectives to help overcome KRAS^G12C inhibitor resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117718"},"PeriodicalIF":6.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933037","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":"Targeted degradation of DDR1 by proteolytic targeting chimera reverses immune exclusion for tumor immunotherapy","authors":"Xiaoyu Wang ,&nbsp;Jiangmeng Zeng ,&nbsp;Shilin Liu ,&nbsp;Fei Qi ,&nbsp;Chao Xin ,&nbsp;Xinyu Li ,&nbsp;Yan Gao ,&nbsp;Dan Fan ,&nbsp;Yuxuan Qu ,&nbsp;Zhiyi Ren ,&nbsp;Jinzhi Liu ,&nbsp;Ruoyu Xue ,&nbsp;Hongwei Chen ,&nbsp;Yong Zhang ,&nbsp;Jing Ha ,&nbsp;Xiangdong Su ,&nbsp;Jinxu Wang","doi":"10.1016/j.ejmech.2025.117750","DOIUrl":"10.1016/j.ejmech.2025.117750","url":null,"abstract":"<div><div>The formation of immune exclusion microenvironment restricts the infiltration of immune cells into the core of tumors. The extracellular domain of the discoidin domain receptor tyrosine kinase 1 (DDR1) protein plays a pivotal role in this process by aligning collagen fibers to remodel the extracellular matrix (ECM), thereby excluding immune cells. Targeted degradation of DDR1 represents a promising approach to suppress the catalytic functions of the protein and remodel the extracellular matrix of DDR1-related tumors. Here, we report the discovery of a selective DDR1 degrader (DP 1), using the proteolysis targeting chimera (PROTAC) approach. Compound DP 1 exhibited potent DDR1 degradation ability with DC₅₀ values reaching nanomolar range across various cell lines. The degradation of DDR1 effectively blocked the downstream signaling pathways, leading to further inhibition of tumor cell migration and invasion. More importantly, the <em>in vivo</em> studies highlighted the therapeutic potential of DDR1 degradation, indicated by the administration of DP 1 could facilitate the infiltration of immune cells into the tumor core which was associated with enhanced tumor apoptosis. In summary, we report a novel DDR1-targeting degrader with efficacious anti-tumor activity and excellent safety profile. Our studies offer a new perspective for cancer immunotherapy by targeting the immune-exclusion microenvironment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117750"},"PeriodicalIF":6.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933038","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":"Prominent supramolecular systems for cancer Therapy: From structural design to tailored applications","authors":"Jiawei Zhang ,&nbsp;Qingya Zhang ,&nbsp;Xiaojia Li ,&nbsp;Yixuan Wei ,&nbsp;Min Qiu ,&nbsp;Huazhe Yang ,&nbsp;Xiaoting Sun","doi":"10.1016/j.ejmech.2025.117754","DOIUrl":"10.1016/j.ejmech.2025.117754","url":null,"abstract":"<div><div>Supramolecular materials represent a powerful class of platforms in cancer diagnosis and therapy, owing to their dynamic architectures, stimuli responsiveness, and high biocompatibility. This review focused on three representative categories—Pillarene-based systems, virus-mimetic nanoparticles (VMNs), and metal-organic frameworks (MOFs)—each offering unique structural and functional properties. Pillarene-based assemblies enable precise host–guest interactions, by being classified into amphiphilic, ionic, and chiral varieties, the robust drug loading and controlled release capabilities of the Pillarene family were emphasized. At the same time, the VMNs, including virus-like particles and virosomes, show power in cancer cell targeting and membrane penetration by emulating natural viral architectures. By discussing the fabrication and application of single-metallic, multi-metallic, and composite MOFs, their potential in multimodal diagnosis and therapy was revealed. In addition, other supramolecular categories, such as cyclodextrin and dendrimers, were introduced as well. We highlighted representative approaches and emerging methods, and comparative perspectives with traditional nanocarriers were included. A critical evaluation of pharmacokinetic behaviors, biosafety concerns, and translational limitations was also proposed, aiming to guide future research in supramolecular cancer nanomedicine. Through an integrative and forward-looking analysis, this review provided a comprehensive framework for understanding and designing supramolecular systems for precision oncology. These emerging nanotechnologies hold promise to reshape cancer medicine by enabling adaptive, targeted, and multifunctional therapeutic strategies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117754"},"PeriodicalIF":6.0,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933040","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":"Design, synthesis and activity evaluation of dithiocarbamate-based L-homoserine lactone derivatives as Gram-negative bacteria quorum sensing inhibitors","authors":"Aichata Maiga ,&nbsp;Li Hong Teng ,&nbsp;Zhen Hao Jie ,&nbsp;Zhang Xue Qing ,&nbsp;Fan Zheng Min ,&nbsp;Lin Zi Wei ,&nbsp;Chunli Wu","doi":"10.1016/j.ejmech.2025.117756","DOIUrl":"10.1016/j.ejmech.2025.117756","url":null,"abstract":"<div><div><em>Pseudomonas aeruginosa</em> (<em>P. aeruginosa</em>) is an important Gram-negative opportunistic pathogen that uses quorum sensing to regulate its virulence and biofilm development, which contributes to its pathogenicity and drug resistance. As a result, focusing on the virulence and pathogenicity of <em>P. aeruginosa</em> through quorum sensing (QS) is considered a possible target for anti-infective therapy. In this work, we discovered new quorum-sensing inhibitors derived from the structural modification of the dithiocarbamate-based <span>l</span>-homoserine lactone derivatives library and the target compound (<strong>10p)</strong> demonstrated significant inhibitory activity against <em>PAO1</em> biofilm (inhibition rate: 86.76 %), pyocyanin (68.05 %), rhamnolipid (34.56 %), LasA protease (61.01 %) and a low inhibitory on elastase production (6.59 %) at 60 μM. Moreover, compound <strong>10p</strong> effectively attenuated <em>P. aeruginosa</em> motility, such as swimming (42.85 %) and swarming (72 %), and demonstrated no toxicity in vitro. The result indicates that compound <strong>10p</strong> may serve as a promising new antibacterial synergist option for treating <em>P. aeruginosa</em> infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117756"},"PeriodicalIF":6.0,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933043","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 potent substrate-type lysine methyltransferase G9a inhibitors for the treatment of sickle cell disease","authors":"Yosuke Nishigaya ,&nbsp;Shohei Takase ,&nbsp;Tatsunobu Sumiya ,&nbsp;Ko Kikuzato ,&nbsp;Takashi Hiroyama ,&nbsp;Yuki Maemoto ,&nbsp;Komei Aoki ,&nbsp;Tomohiro Sato ,&nbsp;Hideaki Niwa ,&nbsp;Shin Sato ,&nbsp;Kentaro Ihara ,&nbsp;Akiko Nakata ,&nbsp;Seiji Matsuoka ,&nbsp;Noriaki Hashimoto ,&nbsp;Ryosuke Namie ,&nbsp;Teruki Honma ,&nbsp;Takashi Umehara ,&nbsp;Mikako Shirouzu ,&nbsp;Hiroo Koyama ,&nbsp;Yukio Nakamura ,&nbsp;Fumiyuki Shirai","doi":"10.1016/j.ejmech.2025.117721","DOIUrl":"10.1016/j.ejmech.2025.117721","url":null,"abstract":"<div><div>Structurally novel inhibitors of the lysine methyltransferase G9a have attracted considerable interest as potential drug candidates for cancer and genetic diseases. Here, a detailed account of potency optimization from early leads <strong>8</strong> and <strong>9</strong> to compound <strong>16g</strong> is presented. Our search for an alternative scaffold for the 4-oxo-4,5,6,7-tetrahydro-1<em>H</em>-indole moiety of compounds <strong>8</strong> and <strong>9</strong> via parallel synthesis led to the identification of the 4-pyridin-4-ylamino phenyl substructure in compound <strong>16g</strong>. This substructure was found to bind to the enzyme in a horizontally flipped manner compared with compound <strong>8</strong> in X-ray crystallographic analysis.</div><div>Compound <strong>16g</strong> is a highly potent G9a inhibitor (IC₅₀ = 0.0020 μM) and structurally distinct from other G9a inhibitors reported in the literature. Importantly, compound <strong>16g</strong> exhibited dose-dependent induction of γ-globin mRNA in HUDEP-2, leading to elevated γ-globin protein levels and F cell numbers in CD34⁺ bone marrow (BM)‒derived hematopoietic cells. Kinetic studies using surface plasmon resonance (SPR) analysis suggested that compound <strong>16g</strong> interacts with G9a via a unique binding mode, as indicated by the markedly higher dissociation constant (K_D) compared to those of compounds <strong>8</strong> and <strong>9</strong>. Interestingly, X-ray crystallographic studies revealed that the binding motif of compound <strong>16g</strong> was quite different from our previous series, including RK-701, and somewhat resembles that of endogenous substrates. Insights obtained in this lead optimization exercise on the association/dissociation constants as well as the binding motifs are expected to help in designing future G9a inhibitors for the treatment of sickle cell disease.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117721"},"PeriodicalIF":6.0,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933042","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}