Novel trisubstituted acridines as human telomeric quadruplex binding ligands

Ungvarsky, Jan; Plsikova, Jana; Janovec, Ladislav; Kovaľ, Ján; Mikeš, Jaromír; Mikesová, Lucia; Harvanová, Denisa; Fedoročko, Peter; Kristián, Pavol; Kašpárková, Jana; Brabec, Viktor; Vojtickova, Maria; Sabolová, Danica; Stramová, Zuzana; Rosocha, Ján; Imrich, Ján; Kožurková, Mária

doi:10.1016/j.bioorg.2014.07.010

Cited by 20 publications

(7 citation statements)

References 59 publications

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“…For example, Shammas and co-workers showed that treatment with hTERT siRNA induced senescence and apoptosis and decreased telomerase activity and telomere length . As anticipated, the biological effects of GTC365 are quite different than the cellular response to DNA damage-inducing G-quadruplex binders, such as BRACO-19 derivatives, RHPS4, TMPyP4, and 307A, which induce accumulation in the cell cycle in both S and G2/M phases. The G2/M phase arrest observed with GTC365 is consistent with known effects of hTERT-modulating mitosis.…”

Section: Discussionmentioning

confidence: 93%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wildtype (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing.We show that promoter mutations exert a detrimental effect on the folding of one of these Gquadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression effects cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and inducing senescence by decreasing telomerase activity and telomere length.We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.3

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Section: Discussionmentioning

confidence: 93%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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“…On the basis of BRACO-19, further optimizations of 3,6,9-trisubstituted acridine compounds were done with systematic variations at the 3-, 6-, and 9-positions [176,177]. Long-term exposure of human breast cancer MCF7 cells to a subset of the most active compounds showed that one compound produced a marked decrease in population growth, accompanied by senescence [176].…”

Section: G-quadruplex Interacting Compoundsmentioning

confidence: 99%

Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

et al. 2019

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G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.

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“…Jain et al reported that both end-stacking and groove-binding were favored after docking dimeric 1,3-phenylene-bis(piperazinyl benzimidazole)s to a 22mer parallel G-quadruplex followed by MD simulations [78]. Ungvarsky et al characterized the binding poses of a novel set of BRACO19 derivatives to the human telomeric parallel G-quadruplex by successfully employing docking and MD simulations [79]. Also, Diveshkumar et al conducted a docking and MD simulation study on various G-quadruplexes (PDB IDs: 2L7V, 2O3M, 1KF1, 143D, and 2MB3) and identified indolyl, methylene-indanone scaffolds which demonstrate selectivity towards parallel promoter G-quadruplexes over telomeric DNA quadruplex or duplex DNA [80].…”

Section: Introductionmentioning

confidence: 99%

Binding of BRACO19 to a Telomeric G-Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

Machireddy

Sullivan

2019

Molecules

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Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19′s binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19′s groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism.

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Novel trisubstituted acridines as human telomeric quadruplex binding ligands

Cited by 20 publications

References 59 publications

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

Binding of BRACO19 to a Telomeric G-Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

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