A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells

Incles, Christopher M; Schultes, Christoph; Kempski, Helena; Koehler, Heike; Kèlland, Lloyd R.; Neidle, Stephen

doi:10.1158/1535-7163.1201.3.10

Cited by 142 publications

(21 citation statements)

References 21 publications

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“…Rapid inhibition of cell growth and proliferation was also accompanied by changes at the telomere itself such as anaphase bridge formation and end-to-end chromosomal fusions. These changes are consistent with telomere end uncapping from associated proteins, ,,− including hPOT1, which binds to the single-stranded overhang and is known to be displaced by quadruplex formation . It has been suggested that the telomerase enzyme complex is physically associated with the extreme 3′ end of the telomeric DNA overhang in cancer cells, with the inference that this association is displaced on quadruplex formation, and thus, telomere attrition is no longer the rate-determining event.…”

Section: Telomeric Quadruplexessupporting

confidence: 59%

“…These events have also been observed in cellulo with a number of quadruplex-binding small molecules, as well as demonstrating telomerase inhibitory activity and telomere shortening. Examples of telomeric quadruplex-binding agents (Figure ) include quinoline-based triazine compounds ( 5 ), BRACO-19 ( 6 , an acridine derivative , ), the perylene derivatives PM2 and PIPER ( 7 ), and more recently, a ruthenium complex with chiral 4-(2,3-dihydroxypropyl)formamide oxoaporphine . The consequences of what is now termed telomere targeting with be discussed further in a subsequent section.…”

Section: Telomeric Quadruplexesmentioning

confidence: 99%

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Quadruplex Nucleic Acids as Novel Therapeutic Targets

2016

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Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters, and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be effectively resolved by helicase action. Mutated helicases in cancer cells are unable to unwind quadruplexes, which are impediments to transcription, translation, or replication, depending on their location within a particular gene. Small molecules that can stabilize quadruplex structures augment these effects and produce cell and proliferation growth inhibition. This article surveys the chemical biology of quadruplexes. It critically examines the major classes of quadruplex-binding small molecules that have been developed to date and the various approaches to discovering selective agents. The challenges of requiring (and achieving) small-molecule targeted selectivity for a particular quadruplex are discussed in relation to the potential of these small molecules as clinically useful therapeutic agents.

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Section: Telomeric Quadruplexessupporting

confidence: 59%

Section: Telomeric Quadruplexesmentioning

confidence: 99%

Quadruplex Nucleic Acids as Novel Therapeutic Targets

2016

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“…Both in vitro and in vivo data strongly support the physiological relevance of this nucleic acid secondary structure at the telomere and the promoter region of oncogenes, a signature guanine-rich region of the genome . Promotor and telomeric G-quadruplexes have been identified as potential therapeutic targets for human cancers and other diseases. − …”

Section: Introductionmentioning

confidence: 82%

Three-Dimensional Structure of RNA Monomeric G-Quadruplex Containing ALS and FTD Related G4C2 Repeat and Its Binding with TMPyP4 Probed by Homology Modeling based on Experimental Constraints and Molecular Dynamics Simulations

Mulholland

Sullivan

Garner

et al. 2019

ACS Chem. Neurosci.

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The G-quadruplex-forming hexanucleotide repeat expansion (HRE), d(G4C2) n , within the human C9orf 72 gene is the root cause for familial amyotrophic lateral sclerosis−frontotemporal dementia (ALS-FTD). A recent study has shown that TMPyP4 has good potential to work as a RNA G-quadruplex binder in treating ALS and FTD. Although the high-resolution structure of the monomeric DNA antiparallel G-quadruplex form of the monomeric hexanucleotide repeat was recently solved, the RNA parallel G-quadruplex structure and its complex with TMPyP4 are not available yet. In this study, we first constructed the homology model for the parallel monomeric RNA G-quadruplex of r(G4C2) 3 G4 based on experimental constraints and the parallel monomeric G-quadruplex DNA crystal structure. Although the G-tetra core of the homology model was stable observed in 15 μs molecular dynamics (MD) simulations, we observed that the loops adopt additional conformations besides the initial crystal conformation, where TMPyP4 binding was found to reduce the loop fluctuation of the RNA monomeric G-quadruplex. Next, we probed the elusive binding behavior of TMPyP4 to the RNA monomeric G-quadruplex. Encouragingly, the binding modes observed are similar to the modes observed in two experimental complexes of a parallel DNA G-quadruplex with TMPyP4. We also constructed a Markov state model to provide insights into the binding pathways. Together, the findings from our study may assist future development of G-quadruplex-specific ligands in the treatment of neurodegenerative diseases like ALS and FTD.

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“…7 BRACO19 (Figure 1), a computationally designed Gquadruplex ligand targeting the parallel-stranded G-quadruplex binding site, 26 inhibits telomerase, causes telomere shortening, and also causes end-to-end chromosomal fusions in cancer cells. 27 It shows significant in vivo anticancer activity in various tumor cell lines (Table S1). 28−43 In addition, BRACO19 also demonstrates broad antiviral activity by stabilizing the Gquadruplexes found in pro-viral DNA.…”

Section: ■ Introductionmentioning

confidence: 99%

Probing the Binding Pathway of BRACO19 to a Parallel-Stranded Human Telomeric G-Quadruplex Using Molecular Dynamics Binding Simulation with AMBER DNA OL15 and Ligand GAFF2 Force Fields

Machireddy

Kalra

Jonnalagadda

et al. 2017

J. Chem. Inf. Model.

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Human telomeric DNA G-quadruplex has been identified as a good therapeutic target in cancer treatment. G-quadruplex-specific ligands that stabilize the G-quadruplex have great potential to be developed as anticancer agents. Two crystal structures (an apo form of parallel stranded human telomeric G-quadruplex and its holo form in complex with BRACO19, a potent G-quadruplex ligand) have been solved, yet the binding mechanism and pathway remain elusive. In this study, we simulated the binding of a free BRACO19 molecule to the apo form of the G-quadruplex using the latest AMBER DNA (OL15) and ligand (GAFF2) force fields. Three binding modes have been identified: top stacking, bottom intercalation, and groove binding. Bottom intercalation (51% of the population) resembles the bottom binding pose in the complex crystal structure very well. The groove binding mode is less stable than the bottom binding mode and is likely to be an intermediate state leading to the bottom binding mode. A flip-insertion mechanism was observed in the bottom intercalation mode, during which flipping of the bases outward makes space for ligand insertion, after which the bases flip back to increase the stability of the complex. In addition to reproducing the base-flipping behavior for some loop residues upon ligand binding, the direct alignment type of the ATAT-tetrad was observed in our simulations for the first time. These successes provide initial support for using this combination of the OL15 and GAFF2 force fields to study quadruplex-ligand interactions.

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A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells

Cited by 142 publications

References 21 publications

Quadruplex Nucleic Acids as Novel Therapeutic Targets

Quadruplex Nucleic Acids as Novel Therapeutic Targets

Three-Dimensional Structure of RNA Monomeric G-Quadruplex Containing ALS and FTD Related G4C2 Repeat and Its Binding with TMPyP4 Probed by Homology Modeling based on Experimental Constraints and Molecular Dynamics Simulations

Probing the Binding Pathway of BRACO19 to a Parallel-Stranded Human Telomeric G-Quadruplex Using Molecular Dynamics Binding Simulation with AMBER DNA OL15 and Ligand GAFF2 Force Fields

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