Structure-Based Approaches Targeting Oncogene Promoter G-Quadruplexes

Ma, Dik‐Lung; Yan, Victor Pui; Leung, Ka‐Ho; He, Hong‐Zhang; Chan, Daniel Shiu‐Hin; Zhong, Hai‐Jing; Leung, Chung‐Hang

doi:10.5772/54809

Cited by 2 publications

(3 citation statements)

References 64 publications

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“…Ferreira et al [40] showed that G-quadruplex binding ligand forms several hydrogen bonds with the G-quadruplex structure for the stable interaction as well as significant p-p interaction. Several papers used H-donor/acceptor as well as hydrophobic centers as a common pharmacophore for virtual screening of G-quadruplex binding ligands [33,41,42].…”

Section: Resultsmentioning

confidence: 99%

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Kang

Park

2014

J Comput Aided Mol Des

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G-quadruplex DNA formed in NHEIII1 region of oncogene promoter inhibits transcription of the genes. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c-MYC. Several hit ligands showed the selective PCR-arresting effects for oligonucleotide containing c-MYC G-quadruplex forming sequence. Among them, three hits selectively inhibited cell proliferation and decreased c-MYC mRNA level in Ramos cells, where NHEIII1 is included in translocated c-MYC gene for overexpression. Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene. In conclusion, combined virtual screening methods were successfully used for discovery of selective c-MYC promoter G-quadruplex binders with anticancer activity.

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Section: Resultsmentioning

confidence: 99%

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Kang

Park

2014

J Comput Aided Mol Des

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“…Apart from that, we found that the piperazine moiety of 4-(piperazin-1-yl)aniline can be N-alkylated at the N 4 position by different-length alkynyl groups (with one to three methylene units) without affecting its ability to bind to G4. This was observed in scaffolds derived from the compound 17 carrying two amino groups at the aromatic ring (43)(44)(45), whereas the activity was abolished in mono-amino derivatives (24)(25)(26). Interestingly, we observed considerable restoration of the G4 stabilizing activity for the click products 34-35 (in PEA) and 38 (in both PEA and FRET), all of which were prepared from the Nalkynylated mono-amino derivatives ( Table 2).…”

Section: Structure-activity Relationshipsmentioning

confidence: 64%

“…In addition, electrostatic interactions between positively charged ligands and negatively charged G4-DNA scaffolds contribute to G4 stabilization. [16] The known c-MYC binders include e. g., the cationic porphyrin TMPyP4, [5] the synthetic fluorescent dye Hoechst 33258, [17][18] quindoline [19][20] and berberine [21] derivatives, carbazoles, [22] perylene derivatives, [23] the fluoroquinolone derivative quarfloxin, [24][25] and the 1,4-dihydroxyanthracene-9,10-dione derivative MYRA-A. [26] More recently, various 4anilinoquinazoline derivatives [27] as well as the crescent-shaped thiazole peptide TH3 [28] were found to down-regulate transcription and expression of the c-MYC gene in HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Target‐Guided Synthesis of Small‐Molecule G‐Quadruplex Stabilizers

et al. 2020

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The formation of a G‐quadruplex motif in the promoter region of the c‐MYC protooncogene prevents its expression. Accordingly, G‐quadruplex stabilization by a suitable ligand may be a viable approach for anticancer therapy. In our study, we used the 4‐(4‐methylpiperazin‐1‐yl)aniline molecule, previously identified as a fragment library screen hit, as a template for the SAR‐guided design of a new small library of clickable fragments and subjected them to click reactions, including kinetic target‐guided synthesis in the presence of a G‐quadruplex forming oligonucleotide Pu24. We tested the clickable fragments and products of click reactions for their G‐quadruplex stabilizing activity and determined their mode of binding to the c‐MYC G‐quadruplex by NMR spectroscopy. The enhanced stabilizing potency of click products in biology assays (FRET, Polymerase extension assay) matched the increased yields of in situ click reactions. In conclusion, we identified the newly synthesized click products of bis‐amino derivatives of 4‐(4‐methylpiperazin‐1‐yl)aniline as potent stabilizers of c‐MYC G‐quadruplex, and their further evolution may lead to the development of an efficient tool for cancer treatment.

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Structure-Based Approaches Targeting Oncogene Promoter G-Quadruplexes

Cited by 2 publications

References 64 publications

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Kinetic Target‐Guided Synthesis of Small‐Molecule G‐Quadruplex Stabilizers

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