Bioorganic & Medicinal Chemistry最新文献

{"title":"Linkers for effective peptide-drug conjugates","authors":"Mohamad Fajar ,&nbsp;Rani Maharani ,&nbsp;Unang Supratman","doi":"10.1016/j.bmc.2025.118510","DOIUrl":"10.1016/j.bmc.2025.118510","url":null,"abstract":"<div><div>Despite their notable anticancer efficacy, many established cancer drugs such as Doxorubicin, camptothecin, paclitaxel, gemcitabine, and methotrexate exhibit limited selectivity to target cancer cells over normal cells. Because these conventional chemotherapeutic agents frequently impact both healthy and cancerous cells, they have high side effects constraining their overall therapeutic index. The challenge arises from their inability to selectively target tumor cells with cytotoxic effects while sparing the surrounding healthy tissues. In response to these limitations, peptide-drug conjugate (PDC) strategies have emerged as an innovative category of targeted therapies designed to improve drug delivery and reduce off-target effects. PDCs utilize the specificity of peptides to deliver cytotoxic agents more accurately to cancer cells, thereby improving therapeutic outcomes and reducing adverse side reactions. PDCs employ peptides that selectively bind to overexpressed receptors on tumor cells, enabling targeted therapy with minimal side effects in cancer patients. To successfully synthesize peptide-drug conjugates, it is essential to have a solid understanding of the active site of the drug, recognition site of the peptide, and where the drug will be release inside the tumor cells. The linker between the drug and the peptide plays a critical role in the stability and release profile of the conjugates, which influence how effectively the drug reaches its target site of action and how it is released within the tumor cells. The choice of linker can determine the pharmacokinetics and bioavailability profiles of PDCs, making it a vital aspect of their design. The review is aimed at providing a comprehensive review of various drug-peptide conjugates with a particular emphasis on the linkers and PDC synthetic methods. Here, we described the advancements PDC chemistries and potential future research areas in drug delivery systems. In addition, we hope to contribute valuable insights into optimizing PDC design for enhanced efficacy in cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118510"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel oxadiazole analogs as anticancer agents: Design, synthesis, in vitro and in vivo biological evaluation, and computer studies of sphingosine kinase inhibitors","authors":"Fuxun Huang ,&nbsp;Xinmei Yang ,&nbsp;Haiyang Wang ,&nbsp;Xiujuan Shi ,&nbsp;Xiaodong Zhao ,&nbsp;Junru Liu ,&nbsp;Yueyang Sun ,&nbsp;Xingbo Song ,&nbsp;Tong Li ,&nbsp;Zhaoyang Li ,&nbsp;Xi Qiu ,&nbsp;Jingtong Feng ,&nbsp;Yuanyuan Liu ,&nbsp;Yuqi Gao ,&nbsp;Yanling Mu ,&nbsp;Zhengguo Cui ,&nbsp;Peng Zhan ,&nbsp;Bo Liu","doi":"10.1016/j.bmc.2025.118487","DOIUrl":"10.1016/j.bmc.2025.118487","url":null,"abstract":"<div><div>Sphingosine kinases (SphKs) have emerged as novel therapeutic targets for treating cancer and inflammation <em>via</em> the SphK/S1P signaling pathway. However, the development of selective SphK inhibitors has been challenging because of their limited specificity. In this study, we used pharmacophore- and docking-based virtual screening to identify the lead compound <strong>DTD-8</strong> (SphK1 IC₅₀ = 79 ± 0.73 μM) and then optimized the structure through structure-based drug design. Our newly synthesized 1,2,4-oxadiazole derivative, compound <strong>22c</strong>, demonstrated selective inhibition against SphK2 (IC₅₀ = 2.24 ± 0.60 μM) over SphK1 (IC₅₀ = 64.20 ± 1.53 μM), representing 28-fold selectivity for SphK2. It also exhibited more potent anticancer activity against DU145 cells (IC₅₀ = 3.09 ± 0.67 μM) than cisplatin (IC₅₀ = 10.67 ± 1.00 μM) owing to its ability to induce S/G2 phase arrest and apoptosis.</div><div>In rats, Compound <strong>22c</strong> showed favorable pharmacokinetic properties, including good metabolic stability (T₁_/₂ = 19.6 h) and high plasma exposure (AUC₀–<em>t</em> = 1077.40 ng h/mL), along with promising <em>in vivo</em> tumor growth inhibition (TGI = 65.96 %). Given its moderate oral bioavailability (F = 54.88 %) and potent anticancer effects, <strong>22c</strong> requires further investigation. These findings provide valuable insights for developing novel SphK2-targeted anticancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118487"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide-based approaches to quorum-sensing disruption: emerging trends and applications in antimicrobial therapy","authors":"Mo Ahamad Khan ,&nbsp;Lechen Zhu ,&nbsp;Hu Zhu","doi":"10.1016/j.bmc.2025.118496","DOIUrl":"10.1016/j.bmc.2025.118496","url":null,"abstract":"<div><div>The rise of antimicrobial resistance (AMR) has outpaced the development of new antibiotics, necessitating alternative therapeutic strategies that do not rely on conventional bactericidal approaches<em>.</em> Quorum-sensing (QS), a bacterial communication system that regulates virulence, biofilm formation and genetic competence, has emerged as a promising non-lethal target. Peptide-based quorum-sensing inhibitors (QSIs) including antimicrobial peptides (AMPs), cyclic dipeptides, and synthetic analogs are gaining recognition for their ability to disrupt QS pathways and attenuate pathogenicity without promoting resistance. This review summarizes recent advancements in peptide-mediated QS interference, covering mechanistic insights, molecular design strategies, and application domains. Natural AMPs such as LL-37 and GH12 modulate QS by altering gene expression or blocking receptor function, while marine-derived cyclic dipeptides act as competitive inhibitors of QS receptors like <em>LasR and CviR.</em> Engineered peptides and peptide-nanocomposite systems have demonstrated improved stability and target specificity, particularly against multidrug-resistant pathogens. Applications span wound healing, prevention of dental biofilms, and prevention of infectious diseases development. However, challenges remain, including peptide instability, low bioavailability, off-target effects, and potential resistance development. Peptide-based QSIs represent a paradigm shift in antimicrobial therapy by disabling bacterial virulence without directly killing cells. Advances in peptide engineering, delivery systems, and synthetic biology are accelerating their clinical and environmental translation. With continued innovation and adapted regulatory frameworks, peptide-based QS inhibition may become a cornerstone of next-generation anti-virulence therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118496"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Redox-cleavable disulfide linker enhances siRNA delivery by prodrug-type bifunctional cell-penetrating peptide” [Bioorg. Med. Chem. 130 (2025) 118383]","authors":"Keita Wakamori,&nbsp;Yuzuki Hashikawa,&nbsp;Hidehito Urata,&nbsp;Shun-ichi Wada","doi":"10.1016/j.bmc.2025.118513","DOIUrl":"10.1016/j.bmc.2025.118513","url":null,"abstract":"","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118513"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide-based antibiotics: structure-driven strategies to tackle toxicity and resistance of antimicrobial peptides","authors":"Maryam Tabarzad ,&nbsp;Maryam Torshabi ,&nbsp;Azadeh Haeri ,&nbsp;Fariba Fathi ,&nbsp;Seyedeh Maryam Mortazavi","doi":"10.1016/j.bmc.2025.118486","DOIUrl":"10.1016/j.bmc.2025.118486","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs) are a prominent weapon that can expand human beings' arsenal against antimicrobial resistance. However, microorganisms can equip themselves against the antimicrobial effects of AMPs. Increasing daily dosing of AMPs to dispel resistance may lead to severe side effects or toxicity. In addition, some poor properties of AMPs, such as rapid degradation and low water solubility, make it difficult to achieve the right therapeutic dose at the target site. To provide more potent and less toxic AMPs, structural modification is one of the promising approaches. This review focuses on five representative AMPs: daptomycin, pexiganan (MSI-78), murepavadin (POL7080), iseganan (IB-367), and omiganan (MBI-226), and involves an analysis of their clinical development, mechanisms of resistance, toxicity profiles, and resultant outcomes. By investigating these specific cases, we derive critical insights into the factors influencing the emergence of resistance, the challenges posed by toxicity, and the structural limitations that have impeded the translation of AMPs into clinical applications. Furthermore, we discuss prospective peptide design strategies that may effectively address these challenges. Notably, we underscore the potential of structure-based strategies, including amino acid substitutions and conjugation with diverse molecular entities (such as small functional groups, synthetic polymers, peptides, and antibiotics), as promising pathways to mitigate these barriers and advance the development of clinically viable AMP therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118486"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomimetic semi-synthesis, structural optimization and anti-HIV activity of naturally scarce eupholathone-, lathyranone- and integerrimine-type Euphorbia diterpenoids","authors":"Wei Cheng ,&nbsp;Peng Wen ,&nbsp;Pei-Yin Song ,&nbsp;Yang Zhang ,&nbsp;Jin-Bu Xu ,&nbsp;Steven De Jonghe ,&nbsp;Dominique Schols ,&nbsp;Feng Gao","doi":"10.1016/j.bmc.2025.118516","DOIUrl":"10.1016/j.bmc.2025.118516","url":null,"abstract":"<div><div>Constructing structural diverse compound libraries based on naturally scarce skeletons is a key challenge in natural product medicinal chemistry research. In this study, structural diversification of three classes of naturally scarce <em>Euphorbia</em> diterpenoids (including 5/7/7/4 eupholathones, 6/11/3 lathyranones, and 5/11 integerrimenes) was achieved via a biomimetic skeleton conversion strategy yielding a library of 72 rare <em>Euphorbia</em> diterpenoid analogues, that was investigated as potential inhibitors of HIV replication. The eupholathone type esters exhibited the most potent anti-HIV activity, emerging as a promising class of anti-HIV agents within the <em>Euphorbia</em> diterpenoids family. Analysis of the structure-activity relationship revealed that the hydroxyl group at C6 of the eupholathone scaffold is a critical position for enhancing anti-HIV potency, with aromatic esters on being particularly favorable. Specifically, the eupholathone ester <strong>2t</strong> showed the best anti-HIV-1 activity, with an EC₅₀ of 1.51 μM and a selectivity index of more than 66.2, suggesting its potential as a candidate for further antiviral drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118516"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel indole-based indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors: design, synthesis, and antidepressant evaluation","authors":"Juan Zhang ,&nbsp;Wen-Jing Gao ,&nbsp;Yu-Xi Zheng ,&nbsp;Jia-Dong Shao ,&nbsp;Nai-Yu Zhang ,&nbsp;Wei Guo ,&nbsp;Shuai Wang ,&nbsp;Qing Zhao ,&nbsp;Kongkai Zhu ,&nbsp;Ming Gao ,&nbsp;Jin-Hai Yu ,&nbsp;Ning Meng ,&nbsp;Cheng-Shi Jiang","doi":"10.1016/j.bmc.2025.118503","DOIUrl":"10.1016/j.bmc.2025.118503","url":null,"abstract":"<div><div>Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor <strong>C-0</strong> (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid <strong>9f</strong> and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid <strong>10f</strong> exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound <strong>10f</strong> demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds <strong>9f</strong> and <strong>10f</strong> had improved <em>in vitro</em> and <em>in vivo</em> pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118503"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polynitrogen-containing compounds as multi-target sEH/FAAH inhibitors: Structure-activity relationship and pharmacological studies","authors":"Amanda Tsang ,&nbsp;Cassandra Yuan ,&nbsp;Manuel Berumen ,&nbsp;Leah Duong ,&nbsp;Karen Gomez ,&nbsp;Shelby Seely ,&nbsp;Alex Salgado ,&nbsp;Adim Rai ,&nbsp;Jo Vistosa ,&nbsp;Edith Morales Munoz ,&nbsp;Marcos E. Ortega ,&nbsp;Christophe Morisseau ,&nbsp;Bruce D. Hammock ,&nbsp;Jake E. Zuckerman ,&nbsp;Joseph Yount ,&nbsp;Davin G. Piercey ,&nbsp;Ram Kandasamy ,&nbsp;Stevan Pecic","doi":"10.1016/j.bmc.2025.118495","DOIUrl":"10.1016/j.bmc.2025.118495","url":null,"abstract":"<div><div>Both soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are involved in degradation of anti-inflammatory and antinociceptive lipids, thus inhibition of these enzymatic pathways represents a novel strategy in the discovery of non-opioid drugs for treating inflammatory pain. We previously discovered several multi-targeted designed ligands and described a pharmacophore necessary for inhibition of both sEH and FAAH. The potential for optimization on the left side of the pharmacophore led us to exploration of different heterocyclic moieties with the hope to keep strong inhibition potencies, but to increase the metabolic stability and solubility of new analogs. Eighteen analogs containing various substituted and unsubstituted pyrimidinyl-, quinoxalinyl- and tetrazolyl- rings are synthesized and tested for inhibition potency in human FAAH, and human, rat and mouse sEH. The structure-activity relationship study revealed quinoxalinyl- analog <strong>4 m</strong>, the most potent dual inhibitor reported to date, with IC₅₀ values of 2.9 nM in human FAAH and 0.7 nM, 39.1 nM and 0.3 nM in human, mouse and rat sEH, respectively. <strong>4 m</strong> showed no binding to opioid and most serotonin receptors and was tested in the human, mouse and rat liver microsomes stability assays where it exhibited good and/or moderate clearance rates. Lastly, we evaluated <strong>4 m</strong> in vivo in a wheel running assay to determine its effects on voluntary locomotor behavior. Both <strong>4 m</strong> and the traditional opioid morphine exhibited significant depression of wheel running after intraperitoneal administration indicating that <strong>4 m</strong> may produce undesirable behavioral effects, which will be the basis for future studies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118495"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Broad-spectrum anti-influenza activity of the NMPA-approved drug Pamiparib is uncovered by virtual docking to the evolutionarily conserved domain of IAV-M2 protein","authors":"Min Chen ,&nbsp;Huifang Jiao ,&nbsp;Dandan Lu ,&nbsp;Wenhuan Chen ,&nbsp;Zhen Yang ,&nbsp;Xue Liang ,&nbsp;Pengcheng Wei ,&nbsp;Kunpeng Liu","doi":"10.1016/j.bmc.2025.118518","DOIUrl":"10.1016/j.bmc.2025.118518","url":null,"abstract":"<div><div>Influenza viruses generate new strains or subtypes through antigenic drift and antigenic shift, leading to the failure of existing antiviral drugs and potentially causing widespread viral infection and influenza epidemics. However, during evolution, certain influenza virus proteins remain unchanged or undergo only minor mutations. Therefore, drugs targeting these evolutionarily conserved viral protein regions may exhibit broad-spectrum antiviral activity across subtypes and against mutations. The purpose of this study is to target the evolutionarily conserved domain of influenza A virus M2 protein and screen for drugs with cross-strain, mutation-resistant, and broad-spectrum antiviral activity. This study used AlphaFold3 to predict the M2 conserved domain structure and employed AutoDock to perform virtual screening of the NMPA database, identifying seven potential candidate drugs. Molecular dynamics simulations indicated that pamiparib exhibits strong affinity for the M2 conserved domain. It demonstrates excellent physiological activity in vitro in inhibiting the replication of H1N1 replication, while showing no effect on other viruses. CETSA experiments confirmed that pamiparib has the potential to bind to the M2 proteins of various influenza virus subtypes. In addition, pamiparib suppresses effectively viral infection in vivo. Ultimately, this study verifies that antiviral drugs designed to target the evolutionarily conserved regions of the influenza virus M2 protein indeed possess broad-spectrum antiviral activity across different strains.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118518"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of lupeol derivatives based on tubulin-targeting strategy: structural modification and correlation analysis of antitumor activity","authors":"Yinxu Zhao ,&nbsp;Liman Hou ,&nbsp;Shuang Tian ,&nbsp;Mengxin Zhu ,&nbsp;Jiale Wu ,&nbsp;Yukun Ma ,&nbsp;Ming Bu ,&nbsp;Yu Lin","doi":"10.1016/j.bmc.2025.118498","DOIUrl":"10.1016/j.bmc.2025.118498","url":null,"abstract":"<div><div>Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound <strong>5l</strong> exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC₅₀) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC₅₀ of human embryonic lung fibroblast MRC-5 cells/IC₅₀ of A549 cells) of 15.39. Mechanistic studies further revealed that compound <strong>5l</strong> is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of −13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound <strong>5l</strong> demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound <strong>5l</strong> holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118498"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}