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Journal articleXu H, Di Antonio M, McKinney S, et al., 2017,
CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours
, Nature Communications, Vol: 8, Pages: 1-18, ISSN: 2041-1723G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).
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Journal articleNicoli F, Roos MK, Hemmig EA, et al., 2016,
Proximity-Induced H-Aggregation of Cyanine Dyes on DNA-Duplexes
, JOURNAL OF PHYSICAL CHEMISTRY A, Vol: 120, Pages: 9941-9947, ISSN: 1089-5639 -
Journal articleHansel-Hertsch R, Beraldi D, Lensing SV, et al., 2016,
G-quadruplex structures mark human regulatory chromatin
, Nature Genetics, Vol: 48, Pages: 1267-1272, ISSN: 1061-4036G-quadruplex (G4) structural motifs have been linked to transcription1,2, replication3 and genome instability4,5 and are implicated in cancer and other diseases6,7,8. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context9,10. Herein we address this through the development of G4 ChIP–seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5′ UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor–induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.
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Journal articleChambers VS, Marsico G, Boutell JM, et al., 2015,
High-throughput sequencing of DNA G-quadruplex structures in the human genome
, Nature Biotechnology, Vol: 33, Pages: 877-881, ISSN: 1087-0156G-quadruplexes (G4s) are nucleic acid secondary structures that form within guanine-rich DNA or RNA sequences. G4 formation can affect chromatin architecture and gene regulation and has been associated with genomic instability, genetic diseases and cancer progression1,2,3,4. Here we present a high-resolution sequencing–based method to detect G4s in the human genome. We identified 716,310 distinct G4 structures, 451,646 of which were not predicted by computational methods5,6,7. These included previously uncharacterized noncanonical long loop and bulged structures8,9. We observed a high G4 density in functional regions, such as 5′ untranslated regions and splicing sites, as well as in genes previously not predicted to contain these structures (such as BRCA2). G4 formation was significantly associated with oncogenes, tumor suppressors and somatic copy number alterations related to cancer development10. The G4s identified in this study may therefore represent promising targets for cancer intervention.
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Journal articleYangyuoru PM, DiAntonio M, Ghimire C, et al., 2015,
Dual Binding of an Antibody and a Small Molecule Increases the Stability of TERRA G‐Quadruplex
, Angewandte Chemie, Vol: 127, Pages: 924-927, ISSN: 0044-8249<jats:title>Abstract</jats:title><jats:p>In investigating the binding interactions between the human telomeric RNA (TERRA) G‐quadruplex (GQ) and its ligands, it was found that the small molecule carboxypyridostatin (cPDS) and the GQ‐selective antibody BG4 simultaneously bind the TERRA GQ. We previously showed that the overall binding affinity of BG4 for RNA GQs is not significantly affected in the presence of cPDS. However, single‐molecule mechanical unfolding experiments revealed a population (48 %) with substantially increased mechanical and thermodynamic stability. Force‐jump kinetic investigations suggested competitive binding of cPDS and BG4 to the TERRA GQ. Following this, the two bound ligands slowly rearrange, thereby leading to the minor population with increased stability. Given the relevance of G‐quadruplexes in the regulation of biological processes, we anticipate that the unprecedented conformational rearrangement observed in the TERRA‐GQ–ligand complex may inspire new strategies for the selective stabilization of G‐quadruplexes in cells.</jats:p>
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Journal articleYangyuoru PM, Di Antonio M, Ghimire C, et al., 2015,
Dual Binding of an Antibody and a Small Molecule Increases the Stability of TERRA G-Quadruplex
, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 54, Pages: 910-913, ISSN: 1433-7851- Author Web Link
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- Citations: 25
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Journal articleLe DD, Di Antonio M, Chan LKM, et al., 2015,
G-quadruplex ligands exhibit differential G-tetrad selectivity
, CHEMICAL COMMUNICATIONS, Vol: 51, Pages: 8048-8050, ISSN: 1359-7345- Author Web Link
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- Citations: 70
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Journal articleDi Antonio M, McLuckie KIE, Balasubramanian S, 2014,
Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a G-Quadruplex Ligand
, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 136, Pages: 5860-5863, ISSN: 0002-7863- Author Web Link
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- Citations: 52
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Journal articleBiffi G, Di Antonio M, Tannahill D, et al., 2014,
Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells
, NATURE CHEMISTRY, Vol: 6, Pages: 75-80, ISSN: 1755-4330- Author Web Link
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- Citations: 435
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Journal articleDi Antonio M, 2014,
Quinone Methides Generation: Applications in Chemical Biology
, CURRENT ORGANIC CHEMISTRY, Vol: 18, Pages: 2-2, ISSN: 1385-2728- Author Web Link
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- Citations: 2
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Journal articleMcLuckie KIE, Di Antonio M, Zecchini H, et al., 2013,
G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells
, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 135, Pages: 9640-9643, ISSN: 0002-7863- Author Web Link
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- Citations: 103
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Journal articleMitchell T, Ramos-Montoya A, Di Antonio M, et al., 2013,
Downregulation of Androgen Receptor Transcription by Promoter G-Quadruplex Stabilization as a Potential Alternative Treatment for Castrate-Resistant Prostate Cancer
, BIOCHEMISTRY, Vol: 52, Pages: 1429-1436, ISSN: 0006-2960- Author Web Link
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- Citations: 21
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Journal articleNikan M, Di Antonio M, Abecassis K, et al., 2013,
An Acetylene-Bridged 6,8-Purine Dimer as a Fluorescent Switch-On Probe for Parallel G-Quadruplexes
, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 52, Pages: 1428-1431, ISSN: 1433-7851- Author Web Link
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- Citations: 42
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Journal articleMurat P, Gormally MV, Sanders D, et al., 2013,
Light-mediated <i>in cell</i> downregulation of G-quadruplex-containing genes using a photo-caged ligand
, CHEMICAL COMMUNICATIONS, Vol: 49, Pages: 8453-8455, ISSN: 1359-7345- Author Web Link
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- Citations: 27
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Journal articleDi Antonio M, Rodriguez R, Balasubramanian S, 2012,
Experimental approaches to identify cellular G-quadruplex structures and functions
, METHODS, Vol: 57, Pages: 84-92, ISSN: 1046-2023- Author Web Link
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- Citations: 38
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Journal articleDoria F, Nadai M, Folini M, et al., 2012,
Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures
, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 10, Pages: 2798-2806, ISSN: 1477-0520- Author Web Link
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- Citations: 90
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Journal articleDi Antonio M, Biffi G, Mariani A, et al., 2012,
Selective RNA Versus DNA G-Quadruplex Targeting by In Situ Click Chemistry
, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 51, Pages: 11073-11078, ISSN: 1433-7851- Author Web Link
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- Citations: 132
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Journal articleMueller S, Sanders DA, Di Antonio M, et al., 2012,
Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells
, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 10, Pages: 6537-6546, ISSN: 1477-0520- Author Web Link
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- Citations: 100
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Journal articleNadai M, Doria F, Di Antonio M, et al., 2011,
Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex
, BIOCHIMIE, Vol: 93, Pages: 1328-1340, ISSN: 0300-9084- Author Web Link
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- Citations: 80
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Journal articlePercivalle C, La Rosa A, Verga D, et al., 2011,
Quinone Methide Generation via Photoinduced Electron Transfer
, JOURNAL OF ORGANIC CHEMISTRY, Vol: 76, Pages: 3096-3106, ISSN: 0022-3263- Author Web Link
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- Citations: 41
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Journal articleVerga D, Nadai M, Doria F, et al., 2010,
Photogeneration and Reactivity of Naphthoquinone Methides as Purine Selective DNA Alkylating Agents
, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 132, Pages: 14625-14637, ISSN: 0002-7863- Author Web Link
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- Citations: 90
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Journal articleDoria F, di Antonio M, Benotti M, et al., 2009,
Substituted Heterocyclic Naphthalene Diimides with Unexpected Acidity. Synthesis, Properties, and Reactivity
, JOURNAL OF ORGANIC CHEMISTRY, Vol: 74, Pages: 8616-8625, ISSN: 0022-3263- Author Web Link
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- Citations: 48
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Journal articleDi Antonio M, Doria F, Richter SN, et al., 2009,
Quinone Methides Tethered to Naphthalene Diimides as Selective G-Quadruplex Alkylating Agents
, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 131, Pages: 13132-13141, ISSN: 0002-7863- Author Web Link
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- Citations: 128
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Journal articleDi Antonio M, Doria F, Mella M, et al., 2007,
Novel naphthalene diimides as activatable precursors of bisalkylating agents, by reduction and base catalysis
, JOURNAL OF ORGANIC CHEMISTRY, Vol: 72, Pages: 8354-8360, ISSN: 0022-3263- Author Web Link
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- Citations: 33
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