Project description:Colorectal cancer (CRC) remains a formidable therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a first-in-class camptothecin derivative engineered for dual-targeting of topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires inefficient metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the hTERT promoter G4, a critical regulator of telomere maintenance and oncogenic transcription. Structural studies reveal 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 exceptional 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 robust DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a promising therapeutic strategy that enhances CRC chemosensitivity, presenting a new framework for combining DNA damage induction with epigenetic silencing in cancer treatment.
Project description:Soybean nested association mapping (NAM) parent lines were compared by CGH to catalog structurally variant (e.g. deletion and duplication) regions among these genotypes. The CGH comparisons reveal reveal putative deletions and duplications among the 41 lines. NAM parent lines were compared through a common reference, Wm82-ISU-01 (this is a sub-line isolated from the cultivar Williams 82 stock). Each NAM parent line was represented by a single individual plant. The reported values show the log2 ratio of the normalized NAM parent line hybridization signals (Cy3) over the normalized Wm82-ISU-01 hybridization signal (Cy5).