European Journal of Medicinal Chemistry最新文献

{"title":"Recent advances in CDC7 kinase inhibitors: Novel strategies for the treatment of cancers and neurodegenerative diseases","authors":"Xi Peng ,&nbsp;Wentao Tang ,&nbsp;Yu Jiang ,&nbsp;Anjiao Peng ,&nbsp;Yao Xiao ,&nbsp;Yiwen Zhang","doi":"10.1016/j.ejmech.2025.117491","DOIUrl":"10.1016/j.ejmech.2025.117491","url":null,"abstract":"<div><div>Cell division cycle 7 (CDC7) plays an indispensable regulatory role in various cellular processes, encompassing the initiation of DNA replication and the maintenance of replication checkpoints. However, dysregulation of CDC7 protein levels is closely associated with the development and progression of several human diseases, particularly cancers and neurodegenerative diseases. Therefore, targeting the CDC7 kinase is deemed a potential avenue for disease management. Currently, a few CDC7 inhibitors have progressed to clinical trials. Nevertheless, limited clinical efficacy coupled with severe adverse reactions necessitates the implementation of innovative technologies to enhance therapeutic effectiveness and minimize adverse events. Herein, we highlight the structure, biological functions and significance in disease progression of CDC7, and discuss the preclinical and clinical states of CDC7 inhibitors. Our focus centers on the structure-activity relationship (SAR) and binding modes of CDC7 inhibitors, offering perspectives on novel CDC7-targeting drugs for clinical application.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117491"},"PeriodicalIF":6.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589869","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":"Rapid discovery of pseudorabies virus inhibitors repurposed from the antimicrobial agent ciprofloxacin","authors":"Lin Wei ,&nbsp;Yun You ,&nbsp;Yang Hu ,&nbsp;Keke Wang ,&nbsp;Honghe Zhao ,&nbsp;Yang Cheng ,&nbsp;Junfei Zhu ,&nbsp;Jun Weng ,&nbsp;Yanliang Ren ,&nbsp;Yuhua Chen ,&nbsp;Meiting Chen ,&nbsp;Xiujuan Chen ,&nbsp;Banbin Xing ,&nbsp;Licheng Bai ,&nbsp;Han Li ,&nbsp;Peng Chen ,&nbsp;Zigong Wei","doi":"10.1016/j.ejmech.2025.117490","DOIUrl":"10.1016/j.ejmech.2025.117490","url":null,"abstract":"<div><div>Pseudorabies virus (PRV) is a significant pathogen impacting swine health and poses high zoonotic risks to humans. Effective antiviral treatments for PRV remain limited, underscoring the need for novel therapeutic strategies. In this study, ciprofloxacin was identified as a repurposed promising candidate with significant <em>in vitro</em> inhibition of PRV replication based on our inference from PNU-183792, an HSV-1 DNA polymerase inhibitor, that quinolones have the potential to act as anti-PRV drugs. Compound <strong>A1</strong> was firstly hopping from ciprofloxacin and PNU-183792, showing more than 500-fold higher anti-PRV activity than ciprofloxacin with an EC₅₀ of 2.21 nM. Then, <strong>C2</strong> was obtained from rapid optimization of replacing the benzyl and cyclopropyl groups of <strong>A1</strong>, which showed excellent inhibition of PRV replication with an EC₅₀ of 0.29 nM and MIC₈₀ in range of 1.6–8 nM. Pharmacokinetic studies demonstrated favorable properties for <strong>C2</strong>, with good plasma exposure following intraperitoneal administration. <em>In vivo</em> studies in Kunming mice showed that <strong>C2</strong> inhibited PRV replication by up to 99 %. These results suggest that quinolone-based inhibitors, particularly <strong>C2</strong>, represent a viable therapeutic approach for the treatment of PRV infections and warrant further preclinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117490"},"PeriodicalIF":6.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589871","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 first-in-class human glycolate oxidase near infrared molecular rotor inhibitors (NIRGOi)","authors":"Sabrina R. Mackinnon ,&nbsp;Christos M. Chatzigiannis ,&nbsp;Stavroula G. Kyrkou ,&nbsp;Murugan Chinnarasu ,&nbsp;Dimitrios A. Diamantis ,&nbsp;Eleftherios Paraskevas Tzakos ,&nbsp;Antonis D. Tsiailanis ,&nbsp;Vasilieios K. Gkalpinos ,&nbsp;Wyatt W. Yue ,&nbsp;Andreas G. Tzakos","doi":"10.1016/j.ejmech.2025.117501","DOIUrl":"10.1016/j.ejmech.2025.117501","url":null,"abstract":"<div><div>Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that affects the metabolism of oxalate leading to formation of renal calculi and end stage kidney failure. Currently, no specific drug exists for PH1 treatment, while human glycolate oxidase (<em>h</em>GO), which influences endogenous oxalate synthesis, is a clinically validated target for PH1 treatment. We envisioned the possibility of exploiting the reported salicylate scaffold as an <em>h</em>GO interactor to develop the first in their class Near Infrared hGO inhibitors, that we termed NIRGOi. These could enable the simultaneous tracking and inhibition of <em>h</em>GO in a single moiety. We encompassed different electron acceptors (A) and 5-formylsalicylic acid, the electron donor (D), as a two in one moiety, to develop three D-A-type NIRGOi, new compounds capable of enhancing their photophysical properties upon interaction with the target protein, <em>h</em>GO. Their photophysical properties verified that the D–A interactions successfully redshifted the emission maxima to wavelengths ranging from 550 nm to 690 nm. Their interaction with <em>h</em>GO was first modelled <em>in silico</em> and then an array of <em>in vitro</em> assays were used to verify their low micromolar efficacy along with the alteration of their photophysical properties upon binding. This study provides new tools, the NIRGOi, that are promising starting points for the development of NIR reporting probes to explore and potentially treat Primary Hyperoxaluria type 1.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117501"},"PeriodicalIF":6.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)pyridine derivatives as novel FLT3-ITD inhibitors","authors":"Shengfei Wu ,&nbsp;Pengjuan Zhao ,&nbsp;Youli Hou ,&nbsp;Lihong He ,&nbsp;Zhongyuan Wang ,&nbsp;Dan Yang ,&nbsp;Yue'e Chai ,&nbsp;Junji Liu ,&nbsp;Yulong Shen ,&nbsp;Aihong Li ,&nbsp;Xing Cui ,&nbsp;Dongsheng Zhao ,&nbsp;Bilan Luo ,&nbsp;Jianta Wang ,&nbsp;Lan Liu ,&nbsp;Weike Liao ,&nbsp;Yu Zhang","doi":"10.1016/j.ejmech.2025.117492","DOIUrl":"10.1016/j.ejmech.2025.117492","url":null,"abstract":"<div><div>FMS-like tyrosine kinase 3 (FLT3) is an ideal drug target for the treatment of acute myeloid leukemia (AML). Although several FLT3 inhibitors have been approved or evaluated in clinical trials, selectivity over c-Kit kinase and FLT3 WT remains a major challenge. Herein, we report a series of 4-(2-fluorophenoxy)pyridine derivatives with potent inhibitory activities against FLT3 internal tandem duplication (FLT3-ITD). The representative compound <strong>13v</strong> inhibited FLT3-ITD kinase and isogenic BaF₃-FLT3-ITD cells with nanomolar IC₅₀ values and achieved selectivity over c-Kit (&gt;53-fold) and FLT WT (19-fold) in transformed BaF₃ cells. In addition, compound <strong>13v</strong> displayed excellent selectivity against FLT3-ITD driven AML cells compared to other leukemia cells, solid tumors, and normal peripheral blood mononuclear cells. Mechanistic studies revealed that <strong>13v</strong> disrupted FLT3 signal transduction and induced G₀/G₁ cell cycle arrest and apoptosis. Moreover, it also showed good developmental profiles in ADME assays. In <em>in vivo</em> studies, <strong>13v</strong> demonstrated desirable pharmacokinetic (PK) profiles and sufficient tumor growth inhibition in a MOLM-13 xenograft model. Taken together, <strong>13v</strong> may represent a starting point for the development of improved FLT3-ITD inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117492"},"PeriodicalIF":6.0,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576192","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":"Exosome/liposome hybrid nanovesicles for enhanced phototherapy and boosted anti-tumor immunity against melanoma","authors":"He Zhou ,&nbsp;Chuanxiu Zhu ,&nbsp;Yingchao Li,&nbsp;Feiyan Zhao,&nbsp;Qixiang Feng,&nbsp;Shangui Liu,&nbsp;Shuangxu Jia,&nbsp;Jianbo Ji,&nbsp;Lei Ye,&nbsp;Guangxi Zhai,&nbsp;Xiaoye Yang","doi":"10.1016/j.ejmech.2025.117485","DOIUrl":"10.1016/j.ejmech.2025.117485","url":null,"abstract":"<div><div>Although phototherapy shows great potential as a safe ablative modality for treatment of cutaneous melanoma, there remain serious flaws restricting its therapeutic outcomes, such as cellular resistance against apoptosis, tumor hypoxia, rewritten cellular metabolism and abnormal angiogenesis. To cope with these challenges, this work combines hemin and IR780 (phototherapy agent) and designs an orchestrated liposome/macrophage-derived exosome hybrid delivery system (named IHEL) for tumor-specific delivery of these two drugs and synchronous tumor microenvironment (TME) reprogramming. As the experimental data suggest, by triggering iron overload and up-regulating HMOX-1, hemin drives a shift from an apoptosis-dominant anti-cancer mode to a combined ferroptosis/apoptosis mode of IR780 treatment, which helps to avoid apoptosis resistance. Also, the catalase-like activity of hemin strengthens PDT effect by alleviating hypoxia. In addition to the above-mentioned enhanced direct cell-killing effect, IHEL also provokes anti-cancer immunity by triggering immunogenic cell death (ICD), intervening glycometabolism and polarizing tumor-associated macrophages (TAMs) in TME to M1-type. This work strongly demonstrated the rationality of IR780/hemin combination and delicately designed immunostimulatory nanocarriers for their tumor-specific delivery, providing both theoretical foundation and practical strategies for advanced anti-cancer phototherapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117485"},"PeriodicalIF":6.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The discovery of novel antimicrobial peptides against drug-resistant bacteria based on fragments fusion strategy","authors":"Chunlan Zeng ,&nbsp;Ziyao Ning ,&nbsp;Yijie Xu ,&nbsp;Long Tian ,&nbsp;Jie Jing ,&nbsp;Longming Chen ,&nbsp;Weifeng Ye ,&nbsp;Jiaqi Han ,&nbsp;Taoran Wang ,&nbsp;Zhao Meng ,&nbsp;Qingbin Meng","doi":"10.1016/j.ejmech.2025.117493","DOIUrl":"10.1016/j.ejmech.2025.117493","url":null,"abstract":"<div><div>Since the escalating prevalence of multidrug-resistant (MDR) bacterial infections posing global health challenges, novel antimicrobial agents are urgently needed. This study designed a series of antimicrobial peptides by fusing two fragments of antimicrobial peptides sC18_4b (1–9) and MSI-78 (10–16). Among these peptides, 13DK_allDab exhibited broad-spectrum antimicrobial efficacy against six different MDR bacterial strains with relatively low MICs. It exerted antibacterial effects through a membrane-disruption mechanism and maintained high stability in serum environment. Moreover, 13DK_allDab displayed low cytotoxicity and hemolysis <em>in vitro</em>, and significant therapeutic efficacy in a mouse acute peritonitis model. These findings demonstrate that 13DK_allDab is a promising antimicrobial agent in counteracting multidrug-resistant bacterial infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117493"},"PeriodicalIF":6.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576195","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":"Exploring chloro-isoxazole compounds inspired on tetrahydrofuran neolignans as promising antileishmanial agents","authors":"Amarith R. das Neves ,&nbsp;Diego B. Carvalho ,&nbsp;Luiz F.P. Pereira ,&nbsp;Rafael F. Rosalem ,&nbsp;Cristiane Y.K. Shiguemoto ,&nbsp;Rafael S. Orofino ,&nbsp;Fernanda Silva ,&nbsp;Gleice K.G. Silva ,&nbsp;Erika P. Machado ,&nbsp;Thalita B. Riul ,&nbsp;Najla M. Kassab ,&nbsp;Gabriela R. Hurtado ,&nbsp;Pamella F. Castilho ,&nbsp;Kelly M.P. Oliveira ,&nbsp;Alda M.T. Ferreira ,&nbsp;Eliane M. Piranda ,&nbsp;Carla C.P. Arruda ,&nbsp;Adriano C.M. Baroni","doi":"10.1016/j.ejmech.2025.117478","DOIUrl":"10.1016/j.ejmech.2025.117478","url":null,"abstract":"<div><div>The present work aims to synthesize and to identify a potential antileishmanial agent from chloro-diphenyl isoxazole methoxylated compounds. We have synthesized ten new chloro-isoxazole analogs inspired by the scaffold of tetrahydrofuran neolignans veraguensin <strong>1a</strong>, grandisin <strong>1b</strong>, and machilin G <strong>1c</strong>. To obtain analogs <strong>4a-4j</strong>, we used a cycloaddition reaction with yields ranging from 45 % to 89 %. All compounds were characterized using Nuclear Magnetic Resonance of ¹H and ¹³C and analyzed by using High-Resolution Mass Spectrometry. The HPLC analysis confirmed that all compounds were more than 95 % pure. Finally, we tested the antileishmanial activity of these analogs against promastigote and intracellular amastigote forms of <em>L. amazonensis</em> in vitro. We conducted tests on murine peritoneal macrophages to determine the cytotoxicity of the analogs. Our findings revealed that <strong>4e</strong> (R₁–R₃ = –OCH₃, X₁ = -Cl, R₄ and R₅ = –OCH₂O-), a hybrid compound of grandisin and machilin G, showed moderate activity on promastigotes (IC₅₀ = 38.1 ± 1.5 μM). <strong>4e</strong> was also effective against intracellular amastigotes with similar IC₅₀ values to AmB-treated control (IC₅₀ = 2.2 ± 0.4 μM and IC₅₀ = 2.0 ± 0.1, respectively). Moreover, it exhibited a selectivity index (SI) for amastigote forms equal to 22.7, higher than the reference drugs we tested. Analog <strong>4e</strong> displayed non-mutagenic potential at all tested concentrations in the Ames test. We also evaluated the therapeutic effect of <strong>4e</strong> on the experimental cutaneous leishmaniasis model with BALB/c mice infected with promastigote forms of <em>L. amazonensis</em> and treated with intralesional (IL) injections. Our study found that mice treated with <strong>4e</strong> had a significant reduction (99.5 % drop) in the footpad tissue parasite load compared to the control group treated with the vehicle. The effect of <strong>4e</strong> was similar, controlling the infection, to that of <em>N</em>-methylglucamine antimonate (Sb, Glucantime, 99.8 % drop), which is a reference treatment. Based on our results, we suggest that chloro-isoxazole analog <strong>4e</strong> shows potential as an antileishmanial agent for treating cutaneous leishmaniasis (CL).</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"290 ","pages":"Article 117478"},"PeriodicalIF":6.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576196","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":"Mitochondrial DNA-targeted triphenylamine-thiophene (TPATP)-derived ligands boost type-I/II photodynamic therapy for triple-negative breast cancer","authors":"Xiao-Dong Wang ,&nbsp;Yong-Si Liu ,&nbsp;Zhi-Ling Liang,&nbsp;Ming-Hao Hu","doi":"10.1016/j.ejmech.2025.117489","DOIUrl":"10.1016/j.ejmech.2025.117489","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is aggressive with poor prognosis. Current strategies include chemotherapy, surgery, and radiotherapy, but face challenges like suboptimal outcomes, low survival, and drug resistance. Thus, novel TNBC therapies are crucial. Activity-based photodynamic therapy (PDT) is a highly regarded cancer treatment strategy known for its spatiotemporal precision, making it a promising option for the treatment of TNBC. In this study, we designed and synthesized three triphenylamine-thiophene (TPATP)-derived ligands binding to mitochondrial DNA G4 (mtG4), which were able to label mitochondria in TNBC cells under red-light excitation, and demonstrated significant phototoxicity through type-I/II process under white-light irradiation, hinting at dual-functional potential for PDT and imaging. The optimal ligand, <strong>TP2</strong>, was demonstrated to disrupt mitochondrial functions under white-light irradiation, leading to MMP loss, ATP reduction, ROS increase, which further triggered significant apoptosis in TNBC cells.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117489"},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575168","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 dihydropteridone derivatives as orally bioavailable PLK1 inhibitors with reduced hERG inhibitory activity for acute myeloid leukemia treatment","authors":"Yunlei Hou ,&nbsp;Shuang Li ,&nbsp;Le Ren ,&nbsp;Long Zhang ,&nbsp;Na Zhang ,&nbsp;Ruifeng Miao ,&nbsp;Qi Huang ,&nbsp;Zhiwei Li ,&nbsp;Changliang Hu ,&nbsp;Zhiguo Xi ,&nbsp;Minghui Tong ,&nbsp;Ping Gong ,&nbsp;Yanfang Zhao ,&nbsp;Yajing Liu ,&nbsp;Jiuyu Liu","doi":"10.1016/j.ejmech.2025.117480","DOIUrl":"10.1016/j.ejmech.2025.117480","url":null,"abstract":"<div><div>Polo like kinase 1 (PLK1) is a serine/threonine kinase that plays an important role in multiple phases of the cell cycle, inhibiting its activity has been considered an effective treatment for acute myeloid leukemia (AML). Here, we reported a series of highly potent PLK1 inhibitors. Among them, compound <strong>WD6</strong> was identified as the most promising PLK1 inhibitor, with an IC₅₀ value of 0.27 nM and greatly reduced hERG affinity, with 12.78 % inhibition at 10 μM. Compound <strong>WD6</strong> displayed significant anti-proliferative activities against MV4-11 (IC₅₀ = 23.3 nM), excellent pharmacokinetic properties (t_1/2 = 7.59 h, AUC_0-t = 29300 ng h mL⁻¹ and <em>F</em> = 35.1 %), good PPB and low risk of drug-drug interactions. <em>In vivo</em>, oral administration of compound <strong>WD6</strong> at a dose of 20 mg/kg effectively suppressed the tumor growth in the MV4−11 xenograft mouse model. Further research indicated that <strong>WD6</strong> exhibited excellent kinase selectivity, arresting MV4-11 cells at G2 phase, inducing apoptosis in a dose-dependent manner and down-regulating the transcription of the proliferation-related oncogene c-MYC. These results showed that compound <strong>WD6</strong> has the potential to be a promising drug candidate for treating AML.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117480"},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569904","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":"Synthesis and preclinical evaluation of an Al18F radio-fluorinated bivalent PD-L1 nanobody","authors":"Yong Huang ,&nbsp;Dongye Zheng ,&nbsp;Chengze Li ,&nbsp;Xixuan Pi ,&nbsp;Senlin Wang ,&nbsp;Zhongjing Li ,&nbsp;Yiluo Li ,&nbsp;Ying Liang","doi":"10.1016/j.ejmech.2025.117487","DOIUrl":"10.1016/j.ejmech.2025.117487","url":null,"abstract":"<div><div>Immunotherapy targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway has achieved remarkable clinical success, but there is a shortage of effective approaches for screening suitable patients. Recently developed PD-L1 nanobody probes have limitations, including limited availability of radionuclides, short tumor retention times, and accumulation in non-target organs. To enhance tumor retention and improve tumor-to-normal tissue contrast, we herein report the synthesis and preclinical evaluation of two Al¹⁸F-labeled bivalent PD-L1 nanobody probes ([¹⁸F]TzTCO-BINb109 and [¹⁸F]RESCA-BINb109). Preliminary results indicated that [¹⁸F]TzTCO-BINb109 had a greater affinity for PD-L1 and better stability than [¹⁸F]RESCA-BINb109. Micro-PET/CT revealed that [¹⁸F]TzTCO-BINb109 uptake in A549-PDL1 tumors peaked at 240 min post-injection (3.19 ± 0.49 %ID/g) and demonstrated sustained retention without in vivo defluorination. In contrast, [¹⁸F]RESCA-BINb109 exhibited shorter tumor retention (at 60 and 240 min, 2.08 ± 0.22 and 1.37 ± 0.26 %ID/g, respectively) and significant defluorination in vivo. Ex vivo biodistribution studies revealed that the tumor uptake of [¹⁸F]TzTCO-BINb109 was consistent with the PET results, with the highest uptake by A549-PDL1 tumor cells (3.43 ± 0.94 %ID/g) compared with H1975 (0.93 ± 0.18 %ID/g) and A549 (0.68 ± 0.12 %ID/g) cells observed at 240 min post-injection. Compared with the previously reported monomeric PD-L1-targeting nanobody probe, [⁶⁸Ga]NOTA-Nb109, [¹⁸F]TzTCO-BINb109 demonstrated enhanced tumor uptake, prolonged retention, and superior tumor-to-normal tissue contrast, contributing to higher imaging quality. These results confirmed that the bivalent PD-L1 nanobody radioligand, [¹⁸F]TzTCO-BINb109, was a promising diagnostic probe for PD-L1 detection, efficacy evaluation, and prescription optimization of immune checkpoint inhibitor therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117487"},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569903","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}