Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase

Dominick, Pamela K.; Keppler, Bernhard K.; Legassie, Jason D.; Moon, Ian K.; Jarstfer, Michael B.

doi:10.1016/j.bmcl.2004.04.055

Cited by 23 publications

(16 citation statements)

References 20 publications

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“…A closer look at the relative affinities of aminoglycosides reveal the same general trend where neomycin was found to have least DC 50 value. The findings presented here correlates very well with the ability of these ligands for telomerase inhibition where neomycin was identified as best of all aminoglycosides studied(62). The results presented in Table2 show an increasing DC 50 value with decreasing charge on the aminoglycoside suggesting that the charge present on them plays a role in their affinity to the quadruplex.…”

Section: Resultssupporting

confidence: 81%

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Aminoglycoside Binding toOxytricha novaTelomeric DNA

et al. 2010

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Telomeric DNA sequences have been at the center stage of drug design for cancer treatment in recent years. The ability of these DNA structures to form four stranded nucleic acid structures, called G-quadruplexes, has been perceived as target for inhibiting telomerase activity vital for the longevity of cancer cells. Being highly diverse in structural forms, these G-quadruplexes are subjects of detailed studies of ligand–DNA interactions of different classes, which will pave the way for logical design of more potent ligands in future. The binding of aminoglycosides were investigated with Oxytricha Nova quadruplex forming DNA sequence (GGGGTTTTGGGG)2. Isothermal Titration calorimetry (ITC) determined ligand to quadruplex binding ratio shows 1:1 neomycin:quadruplex binding with association constants (Ka ) ~ 105M−1 while paromomycin was found to have a two-fold weaker affinity than neomycin. The CD titration experiments with neomycin resulted in minimal changes in the CD signal. FID assays, performed to determine the minimum concentration required to displace half of the fluorescent probe bound, showed neomycin as the best of the all aminoglycosides studied for quadruplex binding. Initial NMR footprint suggests that ligand-DNA interactions occur in the wide groove of the quadruplex. Computational docking studies also indicate that aminoglycosides bind in the wide groove of the quadruplex.

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Section: Resultssupporting

confidence: 81%

“…A recent study by Jarstfer and coworkers suggested aminoglycosides as a class of small molecules for telomerase inhibition (62). In addition to this, our initial findings suggested that aminoglycosides (neomycin specifically), apart from their preference for RNA targets, bind to DNA structures.…”

Section: Resultsmentioning

confidence: 99%

Aminoglycoside Binding toOxytricha novaTelomeric DNA

et al. 2010

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“…Dominick et al found that purified E. aediculatus , T. thermophila , and human telomerase was inhibited by quinacrine [138]. The banding patterns of the telomerase products generated in the presence of quinacrine were, however, not consistent with typical quadruplex stabilizing compounds which tend to cause enrichment of products associated with four repeats of the telomeric sequence [138,139]. Hence the exact process of quinacrine-induced inhibition of telomerase remains unclear.…”

Section: Quinacrine and Telomerasesmentioning

confidence: 99%

Beyond DNA binding - a review of the potential mechanisms mediating quinacrine's therapeutic activities in parasitic infections, inflammation, and cancers

2011

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This is an in-depth review of the history of quinacrine as well as its pharmacokinetic properties and established record of safety as an FDA-approved drug. The potential uses of quinacrine as an anti-cancer agent are discussed with particular attention to its actions on nuclear proteins, the arachidonic acid pathway, and multi-drug resistance, as well as its actions on signaling proteins in the cytoplasm. In particular, quinacrine's role on the NF-κB, p53, and AKT pathways are summarized.

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“…The unique RNA-DNA hybrid that results from interactions between TR and telomeric DNA poses a number of targeting possibilities. In addition to nucleic acid-based blocking therapeutic agents such as imetelstat, there is potential to target TR−DNA duplexes with small intercalating compounds 117,118 . In addition to physically blocking the association of telomerase with the telomere, intercalating compounds could potentially be used as scaffolds for the addition of functional groups with independent activities and/or potential to interact with alternative surfaces of the telomerase holoenzyme, thus providing capacity to alter other properties of the complex.…”

Section: Solution-based Two-dimensional Combinatorial Screeningmentioning

confidence: 99%

New prospects for targeting telomerase beyond the telomere

2016

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Telomerase activity is responsible for the maintenance of chromosome end structures (telomeres) and cancer cell immortality in most human malignancies, making telomerase an attractive therapeutic target. The rationale for targeting components of the telomerase holoenzyme has been strengthened by accumulating evidence indicating that these molecules have extra-telomeric functions in tumour cell survival and proliferation. This Review discusses current knowledge of the biogenesis, structure and multiple functions of telomerase-associated molecules intertwined with recent advances in drug discovery approaches. We also describe the fertile ground available for the pursuit of next-generation small-molecule inhibitors of telomerase.

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Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase

Cited by 23 publications

References 20 publications

Aminoglycoside Binding toOxytricha novaTelomeric DNA

Aminoglycoside Binding toOxytricha novaTelomeric DNA

Beyond DNA binding - a review of the potential mechanisms mediating quinacrine's therapeutic activities in parasitic infections, inflammation, and cancers

New prospects for targeting telomerase beyond the telomere

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