European Journal of Medicinal Chemistry最新文献

{"title":"In silico studies, synthesis, and biological evaluation of novel imidazopyridine-based CYP4Z1 inhibitors targeting breast cancer stem cells.","authors":"Yu Lu, Kailin Chen, Hongqi Wang, Chi Zhang, Xinting Huang, Zihan Wang, Haitao Chen, Miaomiao Niu, Hong Yao, Lufeng Zheng, Shengtao Xu, Qianqian Guo","doi":"10.1016/j.ejmech.2026.118917","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118917","url":null,"abstract":"<p><p>Targeting cancer stem cells (CSCs) has emerged as a promising strategy for cancer therapy and prevention. The human cytochrome P450 enzyme CYP4Z1 has been identified as a potential therapeutic target due to its role in promoting breast cancer stemness. Aiming to develop potent and selective CYP4Z1 inhibitors, our strategy involved systematic structure-activity relationship (SAR) studies of the lead compound XD-2 (1-benzyl-1H-imidazo [4,5-c] pyridine), which led to its structural optimization. A series of derivatives were designed and synthesized to enhance drug-like properties, inhibitory activity, and selectivity. Among all the synthesized compounds, the preferred analog C8, which features an imidazo[4,5-c]pyridine core connected to a terminal butyl group via an amide-containing linker, exhibited the most potent CYP4Z1 inhibitory activity, with an IC₅₀ value of 55.3 nM against CYP4Z1. Molecular docking studies revealed that the introduced side chain extended into the hydrophobic subpocket and the phenyl group established additional aromatic stacking interactions with Trp120. Subsequent in vitro and in vivo biological assessments confirmed that compound C8 potently diminished stemness marker expression, impeded spheroid formation, and attenuated both metastatic potential and tumor-initiating capacity in breast cancer cells. Collectively, these results underscore the promise of C8 as a leading candidate for advancing clinically viable CYP4Z1-targeted therapies in breast cancer.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"314 ","pages":"118917"},"PeriodicalIF":5.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831787","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":"Novobiocin defines an Asn28 allosteric pocket that governs SARS-CoV-2 main protease activity.","authors":"Mohit Bhardwaj, Raushan Anjum, Sheetal Thakur, Pradeep Sharma, Ashok Kumar Patel","doi":"10.1016/j.ejmech.2026.118919","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118919","url":null,"abstract":"<p><p>The repeated outbreaks of coronavirus show how hard it is to keep antiviral effectiveness when the virus mutates. Coronaviruses depend on tightly regulated proteolytic processing mediated by the 3-chymotrypsin-like protease (3CL^pro), making it a key antiviral target. Most current inhibitors engage the catalytic site, an approach that remains vulnerable to resistance driven by active-site mutations. Here, we investigate an alternative strategy based on allosteric regulation of 3CL^pro by targeting a pocket surrounding residue Asn28, previously shown to influence enzymatic activity and dimer stability. Structure-based virtual screening identified novobiocin as a candidate ligand for this region, which lies adjacent to but distinct from the catalytic center. Biophysical experiments showed direct binding of novobiocin to 3CL^pro in solution, with sub-micromolar affinity (K_d ∼ 3 × 10^-7 M). Protease thermal stability and dimeric assembly were lowered by ligand binding. Enzymatic assays revealed a pronounced reduction in catalytic turnover with minimal effects on substrate binding, consistent with an allosteric mechanism of inhibition, and yielded IC₅₀ values of ∼0.5 μM across independent assays. Molecular docking and simulation analyses supported stable binding at the Asn28-associated pocket and revealed localized changes in conformational dynamics. These findings show that novobiocin allosterically inhibits 3CL^pro and identify the Asn28-associated pocket as a relevant target for developing inhibitors with improved resistance to viral evolution.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"314 ","pages":"118919"},"PeriodicalIF":5.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831751","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 preclinical candidate CG-0988, a novel severe acute respiratory syndrome coronavirus 2 3CL protease inhibitor bearing spirooxindole.","authors":"Xiubo Tang, Kai Hou, Xiaowu Chen, Wenyuan Fan, Hao Wu, Jia Meng, Changliang Lu, Gong-Xin He","doi":"10.1016/j.ejmech.2026.118889","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118889","url":null,"abstract":"<p><p>Although coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is no longer a major global pandemic, the disease is still present and may progress into severe respiratory syndrome for many elder or immunocompromised individuals. The treatment options are very limited, and therefore improved therapies for COVID-19 are still needed. Herein, we described a novel class of covalent SARS-CoV-2 3C-like protease (3CL^pro) inhibitors bearing a spirooxindole moiety. By minimizing the peptidomimetic properties of the original structure, we obtained a series of compounds exhibiting excellent potency and high metabolic stability in liver microsomes. This work culminated in the discovery of preclinical candidate CG-0988, which demonstrates excellent antiviral activity (EC50 = 4.0 nM against Omicron EG.5.1). Pharmacokinetic (PK) study of CG-0988 in rats and dogs exhibited favorable PK profiles, with oral availability of 59.2% (in rats) and 94.0% (in dogs), respectively. These findings indicate that CG-0988 is a promising 3CL^pro inhibitor for oral administration, potentially without the need for a PK boosting agent.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"314 ","pages":"118889"},"PeriodicalIF":5.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855504","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":"Rational molecular hybridization of indole-vinyl-substituted 4,5-diphenyloxazolium derivatives enables dual membrane and intracellular targeting for broad-spectrum antibacterial activity.","authors":"Hang Ding, Yangchun Ma, Yan Lan, Yue Kong, Wenlong Zhang, Weijin Chen, Ting Guo, Yi Huang, Fuze Xu, Shutao Ma","doi":"10.1016/j.ejmech.2026.118914","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118914","url":null,"abstract":"<p><p>The escalating crisis of antibiotic resistance poses a severe threat to global public health systems and food safety, which have substantially compromised the therapeutic efficacy of existing antibacterial agents. In this study, a rational molecular hybridization strategy was employed to design and identify a novel amphiphilic small-molecule antibacterial candidate, H14d. In vitro studies demonstrated that H14d exhibits potent broad-spectrum antibacterial activity (MIC = 0.125-4 μg/mL), with MIC values of 0.25 μg/mL against Methicillin-resistant Staphylococcus aureus ATCC43300 (MRSA) and 2 μg/mL against Acinetobacter baumannii ATCC19606. In addition, H14d displayed rapid bactericidal kinetics, a low propensity for resistance development, favorable biosafety profiles, and an exceptional ability to significantly reduce mature bacterial biofilms. Mechanistic investigations revealed that H14d specifically binds to phosphatidylglycerol (PG), a key phospholipid component of bacterial cell membranes, while concurrently inhibiting the essential cell division protein FtsZ, thereby exerting antibacterial activity through a dual-target mode of action. Pharmacokinetic studies showed that H14d displayed stable elimination kinetics (t_1/2 = 10.6-10.9 h) and a large apparent volume of distribution in mice. In vivo efficacy evaluations further demonstrated that H14d outperformed the frontline clinical antibiotic linezolid in a MRSA-infected Galleria mellonella model and multiple murine infection models. Collectively, this study provides valuable insights for the treatment of drug-resistant infections and offers a rational framework for the design and development of next-generation new antibacterial agents.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"314 ","pages":"118914"},"PeriodicalIF":5.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855497","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":"Performance optimization of ultrashort antimicrobial peptides through backbone amide cyclization.","authors":"Ruoxin Tian, Min Yang, Kaixun Cao, Ruiqi Liu, Jianwei Shen, Xiaoshan Huang, Yu Zhang, Yu Rao, Chuan Li, Prateeksha, Zhiyi Liao, Qiumin Lu, Zilei Duan, Ren Lai","doi":"10.1016/j.ejmech.2026.118894","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118894","url":null,"abstract":"<p><p>Antimicrobial resistance demands therapeutics that combine potent activity with low resistance potential. Ultrashort antimicrobial peptides (AMPs) are attractive due to their manufacturability and tunability, but activity is often lost upon sequence minimization because of conformational instability. Here, we establish a conformational engineering strategy based on backbone amide cyclization to restore ultrashort AMP function. Using a snake venom-derived cathelicidin template ZY4, we identified a minimal Trp/Lys/Arg-rich motif and generated the ultrashort cyclic peptide WKR-cyl, which exhibits enhanced antibacterial potency, membrane selectivity, and proteolytic stability compared with linear and disulfide-cyclized analogs. Mechanistically, amide cyclization stabilizes membrane-active conformations and increases hydrophobic driving forces, reducing the energetic barrier for membrane insertion. WKR-cyl preferentially targets peptidoglycan-rich bacterial surfaces, enabling rapid membrane permeabilization and bactericidal activity. WKR-cyl shows potent activity against MRSA, strong anti-biofilm activity, high plasma stability, and minimal resistance induction, and demonstrates therapeutic efficacy in murine MRSA pneumonia and skin infection models, supporting development of clinically translatable ultrashort anti-infective peptides.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"314 ","pages":"118894"},"PeriodicalIF":5.9,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831946","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 Dihydroorotate Dehydrogenase (hDHODH) beyond the barrier: discovery of MEDS700 as blood-brain barrier permeable hDHODH inhibitor","authors":"Stefano Sainas, Chiara Vigato, Paola Circosta, Manuela Zonfrillo, Tiziana Servidei, Marta Alberti, Martina Rescigno, Riccardo Miggiano, Valentina Gaidano, Nicoletta Vitale, Alice Passoni, Alessia Lanno, Barbara Buccinnà, Marco Piccinini, Martina Lorenzati, Serena Gentile, Gianluca Sferrazza, Alessandro Sgambato, Giuseppe Saglio, Marta Giorgis, Marco L. Lolli","doi":"10.1016/j.ejmech.2026.118896","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118896","url":null,"abstract":"Targeting cancer metabolism, particularly <em>de novo</em> nucleotide biosynthesis, has emerged as a promising and innovative therapeutic strategy for both hematologic and solid malignancies, including those of the Central Nervous System (CNS). Glioblastoma cancer stem-like cells are especially vulnerable to pyrimidine synthesis inhibition, highlighting <em>human</em> dihydroorotate dehydrogenase (<em>h</em>DHODH), a rate-limiting enzyme in the <em>de novo</em> pathway, as a potential therapeutic target. <strong>MEDS433</strong> is a best-in-class <em>h</em>DHODH inhibitor, that shows efficacy <em>in vivo</em> after <em>oral</em> administration but lacks efficient penetration of the blood-brain barrier (BBB), limiting its utility against CNS tumors. Its lipophilic analogue <strong>MEDS613</strong> showed enhanced cellular potency, but its poor metabolic stability and rapid conversion to hydroxylated metabolites precluded its future clinical development. In this study, we aimed to design a novel BBB-permeable <em>h</em>DHODH inhibitor, capable of effectively targeting CNS-localized <em>h</em>DHODH. We began by identifying the metabolic <em>soft spots</em> present in the propyloxy side chain of <strong>MEDS613</strong> using this information to develop a metabolically stable analogue, <strong>MEDS700</strong> (compound <strong>3</strong>, as named in the manuscript), that was shown to inhibit <em>h</em>DHODH in the low nanomolar range (IC₅₀ <em>h</em>DHODH 1.5 nM). Subsequently, <strong>MEDS700</strong> was fully profiled, including detailed analysis of its crystallographic binding mode, <em>pan-antitumor</em> activities in cell-based assays and <em>in vitro</em> cytotoxicity on <em>Peripheral Blood Mononuclear Cells</em> (PBMC). An <em>in vivo</em> pharmacokinetic experiment demonstrated that <strong>MEDS700</strong> was able to cross the <em>blood-brain barrier,</em> maintaining therapeutically relevant intracerebral concentrations for up to 24 hours after oral administration. Our findings establish <strong>MEDS700</strong> as a potent, safe, metabolically stable <em>h</em>DHODH inhibitor, indicating it as a promising candidate for the treatment of hard-to-reach brain tumors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147756143","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":"Copper(II) Complexes of Indolo[2,3-c]quinoline-Derived Schiff Bases: Insight into the Mechanism of their Antiproliferative Activity","authors":"Felix Bacher, Christian Madejski, Irina Kuznetcova, Orsolya Dömötör, Béla Gyurcsik, Zeyad H. Nafaee, Nóra Igaz, Csenge Bocz, Bálint Péntek, Mónika Kiricsi, Petra Raptova, Alexandru-Constantin Stoica, Michaela Hejl, Michael A. Jakupec, Samah Mutasim Alfadul, Maria V. Babak, Peter Rapta, Jóhannes Reynisson, Lenka Sindlerova, Éva A. Enyedy, Ernest Hamel, Vladimir B. Arion","doi":"10.1016/j.ejmech.2026.118882","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118882","url":null,"abstract":"Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indolo[2,3-<ce:italic>c</ce:italic>]quinoline derivatives <ce:bold>HL</ce:bold><ce:sup loc=\"post\"><ce:bold>1</ce:bold></ce:sup>–<ce:bold>HL</ce:bold><ce:sup loc=\"post\"><ce:bold>8</ce:bold></ce:sup> and their copper(II) complexes were synthesized, comprehensively characterized and tested for antiproliferative activity against MDA-MB-231, MCF-7, MCF-7 KCR, A549 and DU-145 cancer cells and compared to known isomeric indolo[3,2-<ce:italic>c</ce:italic>]quinolines (<ce:bold>HL</ce:bold><ce:sup loc=\"post\"><ce:bold>11</ce:bold></ce:sup><ce:bold>–HL</ce:bold><ce:sup loc=\"post\"><ce:bold>14</ce:bold></ce:sup> and <ce:bold>11–14</ce:bold>). The Cu(II) complexes were generally as active, or slightly more so, than the proligands. Lead compounds <ce:bold>HL</ce:bold><ce:sup loc=\"post\"><ce:bold>8</ce:bold></ce:sup> and <ce:bold>8</ce:bold> showed superior anticancer activity compared to isomers <ce:bold>HL</ce:bold><ce:sup loc=\"post\"><ce:bold>14</ce:bold></ce:sup> and <ce:bold>14</ce:bold>, respectively. Complex <ce:bold>8</ce:bold> was superior to <ce:bold>HL</ce:bold><ce:sup loc=\"post\"><ce:bold>8</ce:bold></ce:sup> in ROS generation in A549 cells, induced mitochondrial dysfunction as evidenced by JC-1 staining, induced lactate dehydrogenase release in medium, inhibited DNA synthesis and triggered apoptosis. DNA-binding studies, supported by molecular docking calculations, showed strong affinity of the compounds for double stranded DNA, to which they bind by intercalation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147736522","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":"Identification of a novel HNF4α agonist regulating abnormal metabolism.","authors":"Tzumei Wang, Chaochun Wei, Jingwen Li, Xinyi Zhao, Kaixuan Wang, Xing Peng, Xiaodong Dou, Yameng Liu, Chao Wang, Ning Jiao","doi":"10.1016/j.ejmech.2026.118864","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118864","url":null,"abstract":"<p><p>Hepatocyte nuclear factor 4 alpha (HNF4α) is a key nuclear receptor involved in liver function and metabolic regulation, making it a potential therapeutic target for lipid-metabolism disorders. Combining time-resolved fluorescence resonance energy transfer (TR-FRET) high-throughput screening with a diffusion-based structure-guided generative design workflow (DiffSBDD), we identified and prioritized a series of compounds with HNF4α agonist-like activity. Among them, (Z)-19 showed good HNF4α activation with an EC₅₀ of 9.2 μM, outperforming the reference agonist N-trans-caffeoyltyramine (NCT; EC₅₀ = 129.6 μM). Surface plasmon resonance (SPR) supported a direct interaction with HNF4α (K_D = 4.6 μM). In HepG2 cells, (Z)-19 reduced triglyceride and total cholesterol accumulation with minimal cytotoxicity and exhibited ferroptosis-protective activity, with a response profile differing from that of NCT. In a hyperlipidemia mouse model, (Z)-19 lowered plasma triglyceride and total cholesterol levels, indicating encouraging in vivo efficacy. Additionally, all-atom molecular dynamics (MD) simulations supported a possible binding mode characterized by persistent hydrogen-bonding and hydrophobic contacts within the ligand-binding domain, and yielded favorable binding-free-energy estimates consistent with the experimental potency ranking. Together, these results identify (Z)-19 as a promising starting point for further optimization and mechanistic investigation of compounds that modulate HNF4α.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"314 ","pages":"118864"},"PeriodicalIF":5.9,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831812","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":"Erratum to 'The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist' [Eur. J. Med. Chem. 210 (2021) 113087].","authors":"Michael Moir, Samuel Lane, Andrew P Montgomery, David Hibbs, Mark Connor, Michael Kassiou","doi":"10.1016/j.ejmech.2026.118839","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118839","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":" ","pages":"118839"},"PeriodicalIF":5.9,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643533","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 ENPP1 inhibitors with benzotriazole core for cancer immunotherapy","authors":"Junghwan Choi ,&nbsp;Sunwoo Lee ,&nbsp;Yong-Yea Park ,&nbsp;Jihun Kim ,&nbsp;Haein Kim ,&nbsp;Kyeongwon Moon ,&nbsp;Sunyoung Park ,&nbsp;Eun Kyung Yoo ,&nbsp;Chang Won Min ,&nbsp;Hyouk Woo Lee ,&nbsp;Hyun-Ju Park ,&nbsp;Pargat Singh ,&nbsp;Sungjoon Kim ,&nbsp;Chan Sun Park ,&nbsp;In Su Kim","doi":"10.1016/j.ejmech.2026.118666","DOIUrl":"10.1016/j.ejmech.2026.118666","url":null,"abstract":"<div><div>The cGAS-STING signaling pathway is an essential mechanism in the recruitment and activation of innate and adaptive immune cells to exert an antitumor response in cancer immunotherapy. cGAMP is a crucial immunotransmitter, which is potentially degraded by ENPP1, resulting in the deactivation of STING-mediated antitumor immune responses. We herein describe the design, synthesis, and biological evaluation of novel ENPP1 inhibitors containing a benzotriazole core and a sulfonimidamide Zn binder. Notably, compound <strong>44a</strong> demonstrated potent and selective ENPP1 inhibition with an IC₅₀ value of 13.1 nM and effectively activated the STING pathway in HCT116-Dual™ cells. Additionally, compound <strong>44a</strong> exhibited a notable release of cytokines in THP-1 cell lines, thereby enhancing the innate immune response. The oral administration of compound <strong>44a</strong> displayed remarkable antitumor efficacy in the MC38 syngeneic mouse model without notable toxicity. Therefore, compound <strong>44a</strong> can be considered a promising candidate as a selective and orally bioavailable ENPP1 inhibitor.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"307 ","pages":"Article 118666"},"PeriodicalIF":5.9,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153257","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}