{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:31:43Z","timestamp":1786422703150,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81572926"],"award-info":[{"award-number":["81572926"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81703349"],"award-info":[{"award-number":["81703349"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["81572926"],"award-info":[{"award-number":["81572926"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["81703349"],"award-info":[{"award-number":["81703349"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"crossref","award":["2024A1515013282"],"award-info":[{"award-number":["2024A1515013282"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The urgent need for novel glioblastoma (GBM) therapies has motivated the exploration of EGFR G-quadruplex (G4) targeting, which suppresses oncogene transcription independently of kinase activity. However, existing EGFR G4 ligands lack subtype selectivity. Through computer-aided design and systematic bioisosteric modifications of the 1H-imidazo[4,5-f][1,10]phenanthroline scaffold, we synthesized a series of derivatives. We evaluated their G4 interactions by molecular docking, UV-Vis, FRET, ITC, and CD. Compound 3, bearing a 6-bromopiperonyl group, exhibited nanomolar affinity for EGFR G4 (Kd = 102 nM) with ~146-fold selectivity over K-Ras G4, stabilizing it via end-stacking. It potently inhibited U87-MG glioblastoma cell proliferation (IC50 = 0.49 \u03bcM), with a wide safety margin relative to normal HMC3 microglia (safety index = 14.18). Mechanistically, compound 3 triggered DNA damage, mitochondrial oxidative stress, and sequential multi-organelle damage to mitochondria, lysosomes, and the endoplasmic reticulum, while impairing cell migration and invasion. These findings establish compound 3 as a uniquely selective EGFR G4 stabilizer, offering a promising multi-organelle-damage strategy for glioblastoma therapy.<\/jats:p>","DOI":"10.3390\/antiox15080984","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:38:09Z","timestamp":1786361889000},"page":"984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computer-Aided Discovery of EGFR G-Quadruplex Targeting Phenanthroimidazole Derivatives Inducing Concurrent Multi-Organelle Damage in Glioblastoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Mengjiao","family":"She","sequence":"first","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhan","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanyu","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renshan","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zeng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7374-2020","authenticated-orcid":false,"given":"Chunling","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wu","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Small Molecule Drugs, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlan","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Mei","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangdong Engineering Technology Research Centre of Molecular Probe and Biomedicine Imaging, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"Engineering Research Center of Small Molecule Drugs, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"Department of Oncology, The Second Clinical Medial School of Gaungdong Pharmaceutical University, Guangdong Second Provincial General Hospital, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/S0140-6736(23)01054-1","article-title":"Primary brain tumours in adults","volume":"402","author":"Geurts","year":"2023","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1016\/j.apsb.2021.12.019","article-title":"Therapeutic strategies of glioblastoma (GBM): The current advances in the molecular targets and bioactive small molecule compounds","volume":"12","author":"Liu","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1158\/2159-8290.CD-20-1474","article-title":"Diffuse Glioma Heterogeneity and Its Therapeutic Implications","volume":"11","author":"Nicholson","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e08142","DOI":"10.1002\/smll.202508142","article-title":"Aggressive Glioblastoma Cells Enhance the Migratory Persistence and Velocity of Less Aggressive Cells to Promote Tumor Dissemination","volume":"22","author":"Mohand","year":"2026","journal-title":"Small"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.eng.2024.03.015","article-title":"DNA G-Quadruplexes as Targets for Natural Product Drug Discovery","volume":"36","author":"Wang","year":"2024","journal-title":"Engineering"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16228","DOI":"10.1021\/jacs.3c05214","article-title":"Structure of the Major G-Quadruplex in the Human EGFR Oncogene Promoter Adopts a Unique Folding Topology with a Distinctive Snap-Back Loop","volume":"145","author":"Liu","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/s41586-021-04393-3","article-title":"Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias","volume":"602","author":"Hu","year":"2022","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/s41392-020-00251-2","article-title":"Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth","volume":"5","author":"Yao","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1038\/s41556-022-00962-4","article-title":"EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation","volume":"24","author":"Guo","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"152742","DOI":"10.1016\/j.ijbiomac.2026.152742","article-title":"Targeting the EGFR G-quadruplex DNA in liver cancer: Discovery of alkynyl-modified phenanthroimidazole derivatives as potent stabilizers","volume":"369","author":"Chen","year":"2026","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"122481","DOI":"10.1016\/j.lfs.2024.122481","article-title":"G-quadruplex ligands in cancer therapy: Progress, challenges, and clinical perspectives","volume":"340","author":"Figueiredo","year":"2024","journal-title":"Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20210214","DOI":"10.1002\/EXP.20210214","article-title":"Methodological advances of bioanalysis and biochemical targeting of intracellular G-quadruplexes","volume":"2","author":"Teng","year":"2022","journal-title":"Exploration"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"gkaf543","DOI":"10.1093\/nar\/gkaf543","article-title":"Pyridine-bis(benzimidazole) induces DNA damage at G-quadruplex loci and promotes synthetic lethality with DNA repair inhibition","volume":"53","author":"Yan","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18724","DOI":"10.1021\/acs.jmedchem.4c00797","article-title":"Discovery of Arene Ruthenium(II) Complexes as Potential VEGF Inhibitors for Glioblastoma Metastasis Suppression","volume":"67","author":"Yuan","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Falanga, A.P., Terracciano, M., Oliviero, G., Roviello, G.N., and Borbone, N. (2022). Exploring the Relationship between G-Quadruplex Nucleic Acids and Plants: From Plant G-Quadruplex Function to Phytochemical G4 Ligands with Pharmaceutic Potential. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112377"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1016\/j.drudis.2020.07.005","article-title":"Advancing computer-aided drug discovery (CADD) by big data and data-driven machine learning modeling","volume":"25","author":"Zhao","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_17","first-page":"19581","article-title":"Electric Field-Responsive Gold Nanoantennas for the Induction of a Locoregional Tumor pH Change Using Electrolytic Ablation Therapy","volume":"18","author":"Joe","year":"2024","journal-title":"ACS Nano"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"140556","DOI":"10.1016\/j.ijbiomac.2025.140556","article-title":"Diphenylaminothiophen-derived fluorescent ligands targeting mitochondrial DNA G-quadruplexes potentially for triple-negative breast cancer therapy","volume":"302","author":"Wang","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14046","DOI":"10.1021\/acs.jmedchem.1c01215","article-title":"Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design","volume":"64","author":"Subbaiah","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1021\/prechem.4c00019","article-title":"A Hydrogen-Bonded, Hexagonally Networked, Layered Framework with Large Aperture Designed by Structural Synchronization of a Macrocycle and Supramolecular Synthon","volume":"2","author":"Yoshimura","year":"2024","journal-title":"Precis. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sun, J., Wang, Y., Huang, Y., and Chen, Z. (2026). G-Quadruplex Unwinding Molecular Mechanisms by Helicases and Their Applications. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27041629"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1021\/jacsau.1c00284","article-title":"Beyond Conformational Control: Effects of Noncovalent Interactions on Molecular Electronic Properties of Conjugated Polymers","volume":"1","author":"Liu","year":"2021","journal-title":"JACS Au"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e202501443","DOI":"10.1002\/anie.202501443","article-title":"Conformational Change in a Four-Tetrad DNA G-Quadruplex upon Intercalation of a Small-Molecule Ligand PyDH2","volume":"64","author":"Martin","year":"2025","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.31635\/ccschem.021.202101357","article-title":"Exploring Sequence Space to Design Controllable G-Quadruplex Topology Switches","volume":"4","author":"Chen","year":"2022","journal-title":"CCS Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11878","DOI":"10.1021\/jacs.2c04775","article-title":"Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes","volume":"144","author":"Liu","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9037","DOI":"10.1038\/s41467-024-53159-8","article-title":"The homeodomain regulates stable DNA binding of prostate cancer target ONECUT2","volume":"15","author":"Chatterjee","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16166","DOI":"10.1021\/jacs.3c04810","article-title":"Stacking Interactions and Flexibility of Human Telomeric Multimers","volume":"145","author":"Rosi","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1038\/s41587-024-02487-7","article-title":"Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system","volume":"43","author":"Wang","year":"2025","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12964-025-02135-w","article-title":"The inducible role of autophagy in cell death: Emerging evidence and future perspectives","volume":"23","author":"Huang","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.1038\/s41467-020-16926-x","article-title":"DNA double-strand breaks induce H2Ax phosphorylation domains in a contact-dependent manner","volume":"11","author":"Collins","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41580-021-00404-3","article-title":"Cell cycle control in cancer","volume":"23","author":"Matthews","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100030","DOI":"10.1016\/j.pharmr.2024.100030","article-title":"Cell cycle dysregulation in cancer","volume":"77","author":"Glaviano","year":"2025","journal-title":"Pharmacol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1016\/j.apsb.2022.03.020","article-title":"Non-apoptotic cell death-based cancer therapy: Molecular mechanism, pharmacological modulators, and nanomedicine","volume":"12","author":"Wang","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"eadu9555","DOI":"10.1126\/sciadv.adu9555","article-title":"DNA damage response pathway regulates Nrf2 in response to oxidative stress","volume":"11","author":"Jiang","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102797","DOI":"10.1016\/j.redox.2023.102797","article-title":"Metabolic reprogramming, oxidative stress, and pulmonary hypertension","volume":"64","author":"Pokharel","year":"2023","journal-title":"Redox Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.actbio.2023.03.017","article-title":"Biomimetic nanoplatform with H2O2 homeostasis disruption and oxidative stress amplification for enhanced chemodynamic therapy","volume":"162","author":"Fu","year":"2023","journal-title":"Acta Biomater."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e20031","DOI":"10.1002\/advs.202520031","article-title":"Multi-Organelle Stress-Induced Paraptosis by a ROS-Amplifying Nanocatalyst for Enhanced Cancer Immunotherapy","volume":"13","author":"Yu","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1161\/CIRCRESAHA.124.323800","article-title":"Mitochondrial Structure and Function in Human Heart Failure","volume":"135","author":"Hinton","year":"2024","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13024-022-00555-7","article-title":"Crosstalk of organelles in Parkinson\u2019s disease\u2014MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes","volume":"17","author":"Lang","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41420-023-01353-w","article-title":"Synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles","volume":"9","author":"Zhang","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e2412246122","DOI":"10.1073\/pnas.2412246122","article-title":"Stress-induced translocation of the endoplasmic reticulum chaperone GRP78\/BiP and its impact on human disease and therapy","volume":"122","author":"Lee","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yang, D.L., Li, Y., Ma, S.Q., Zhang, Y.J., Huang, J.H., and He, L.J. (2023). Compound 275# Induces Mitochondria-Mediated Apoptosis and Autophagy Initiation in Colorectal Cancer Cells through an Accumulation of Intracellular ROS. Molecules, 28.","DOI":"10.3390\/molecules28073211"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12943-025-02267-0","article-title":"Glioblastoma multiforme: Insights into pathogenesis, key signaling pathways, and therapeutic strategies","volume":"24","author":"Pouyan","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/s41419-020-2381-8","article-title":"MOB2 suppresses GBM cell migration and invasion via regulation of FAK\/Akt and cAMP\/PKA signaling","volume":"11","author":"Jiang","year":"2020","journal-title":"Cell Death Dis."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/984\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:19:04Z","timestamp":1786421944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/984"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,8]]},"references-count":44,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["antiox15080984"],"URL":"https:\/\/doi.org\/10.3390\/antiox15080984","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,8]]}}}