9VA0

Solution NMR structures of hTERT DNA G-quadruplexes (G4s) in complex with small molecule CPT-11

Summary for 9VA0

• Entry DOI: 10.2210/pdb9va0/pdb
• Descriptor: DNA (5'-D(*AP*AP*TP*GP*GP*GP*AP*GP*GP*GP*TP*CP*TP*GP*GP*GP*AP*GP*GP*GP*CP*C)-3'), POTASSIUM ION, (4S)-4,11-DIETHYL-4-HYDROXY-3,14-DIOXO-3,4,12,14-TETRAHYDRO-1H-PYRANO[3',4':6,7]INDOLIZINO[1,2-B]QUINOLIN-9-YL 1,4'-BIPIPERIDINE-1'-CARBOXYLATE (3 entities in total)
• Functional Keywords: g-quadruplexes, topoisomerase i, cpt-11, irinotecan, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 7603.34

Authors

Zeng, L. (deposition date: 2025-06-02, release date: 2026-02-11, Last modification date: 2026-05-06)

Primary citation

Li, Y.,Ji, D.,Jia, Y.,Liang, Y.,Wei, E.,Gao, C.,Li, Y.,Zeng, C.,Wang, L.,Wang, C.,Guo, Z.,Zhang, Y.,Zhou, M.M.,Wu, D.,Zeng, L.
Dual targeting of topoisomerase I and DNA G-quadruplexes enhances senescence and chemosensitivity in colorectal cancer.
Commun Biol, 9:-, 2026

PubMed Abstract: Colorectal cancer (CRC) remains a therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a camptothecin derivative engineered to target both topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the hTERT promoter G4, a regulator of telomere maintenance and oncogenic transcription. Structural studies reveal that the crescent-shaped scaffold of ZBH-01 π-π stacks onto the external G-tetrad of the hTERT G4, displacing SP1/MYC transcription factors and suppressing hTERT expression. Functionally, ZBH-01 demonstrated improved efficacy in chemoresistant models, exhibiting 14-fold and 7-fold greater efficacy than CPT-11 and SN-38 respectively in cisplatin-resistant cells, and outperforming CPT-11 by 61-fold and SN-38 by 2.4-fold in 5-FU-resistant models. By concurrently disrupting DNA repair through TOP1-trapping and transcriptional adaptation via G4-stabilization, ZBH-01 induced DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a potential therapeutic strategy to enhance CRC chemosensitivity, presenting a new framework for combining DNA damage induction with transcription modulation.

PubMed: 41803560
DOI: 10.1038/s42003-026-09801-w

Experimental method

SOLUTION NMR