Recent Development of c-myc G-Quadruplex Ligands

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In this review, we summarize recent findings in the development of c-myc G-quadruplex ligands. Several features such as expanded aromatic rings, flexible molecules, dinuclear metal complexes, oligomers and G-quartet based ligands have been demonstrated to be advantageous for providing higher selectivity towards the c-myc G-quadruplex over duplex structures. High throughput screening methods including competition dialysis, G4 FID, FRET-based melting assay, direct ELISA and in silico virtual screening for analyzing the interaction between the ligands and the c-myc G-quadruplex are discussed. In particular, in silico virtual screening has been demonstrated to be a valuable means for the discovery of selective G-quadruplex ligands. Using this approach, ligands selective for the c-myc G-quadruplex have been successfully identified
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c-myc G-quadruplex; G-quadruplex Ligands; High Throughput; Virtual Screening

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T.A. Brook and L.H. Hurley., The Role of Supercoiling in Transcriptional Control of MYC and its Importance in Molecular Therapeutics , Nat Rev Cancer, Volume 9,(Issue 12) December 2009, Pages 849-861.

C. Grandori, S. M. Cowley, et al., The MYC/MAX/MAD Network and the Transcriptional Control of Cell Behavior, Annual Review of Cell and Developmental Biology, Volume 16, Novermber 2000, Pages 653-699.

S. Pelengaris and M. Khan. The Many Faces of c-MYC, Archives of Biochemistry and Biophysics, Volume 416, (Issue 2) August 2003, Pages 129-136.

S. Pelengaris and M. Khan, The c-MYC oncoprotein as a treatment target in cancer and other disorders of cell growth, Expert Opinion on Therapeutic Targets, October 2003, Volume 7, (Issue 5), Pages 623-642.

M. D. Cole and S. B. McMahon, The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation, Oncogene, May 1999, Volume 18, Pages 2916-2924.

C. A. Spencer, M. Groudine et al., Control of c-myc Regulation in Normal and Neoplastic Cells, Advances in Cancer Research, Academic Press, 1991, Pages 1-48.

L. M. Facchini and L. Z. Penn, The Molecular Role of Myc in Growth and Transformation: Recent Discoveries Lead to New Insights, The Journal of the Fredration of American Societies for Experimental Biology, June 1998, Volume 12, (Issue 9), Pages 633-651.

O. Sakatsume, H. Tsutsui, et al., Binding of THZif-1, a MAZ-like Zinc Finger Protein to the Nuclease-hypersensitive Element in the Promoter Region of the c-MYC Protooncogene, The Journal of Biological Chemistry, December 1996, Volume 271, (Issue 49), Pages 31322-31333.

E. H. Postel, S. E. Mango et al., A Nuclease-hypersensitive Element of the Human c-myc Promoter Interacts with a Transcription Initiation Factor, Molecular and Cellular Biology, November 1989, Volume 9, (Issue 11), Pages 5123-5133.

U. Siebenlist, L. Hennighausen et al., Chromatin Structure and Protein Binding in the Putative Regulatory Region of the c-myc Gene in Burkitt Lymphoma, Cell, June 1984, Volume 37, (Issue 2), Pages 381-391.

T. C. Boles and M. E. Hogan, DNA Structure Equilibria in the Human c-myc Gene, Biochemistry, January 1987, Volume 26, (Issue 2), Pages 367-376.

T. Tomonaga and D. Levens, Activating Transcription from Single Stranded DNA, Proceedings of the National Academy of Sciences, June 1996, Volume 93, (Issue 12), Pages 5830-5835.

J. Shklover, P. Weisman-Shomer et al., Quadruplex Structures of Muscle Gene Promoter Sequences Enhance in vivo MyoD-dependent Gene Expression, Nucleic Acids Research, April 2010, Volume 38, (Issue 7), Pages 2369-2377.

S. Etzioni, A. Yafe et al., Homodimeric MyoD Preferentially Binds Tetraplex Structures of Regulatory Sequences of Muscle-specific Genes, The Journal of Biological Chemistry, July 2005, Volume 280, (Issue 29), Pages 26805-26812.

J. Shklover, S. Etzioni et al., MyoD Uses Overlapping but Distinct Elements to Bind E-box and Tetraplex Structures of Regulatory Sequences of Muscle-specific Genes, Nucleic Acids Research, October 2007, Volume 35, (Issue 21), Pages 7087-7095.

A. Yafe, J. Shklover et al., Differential Binding of Quadruplex Structures of Muscle-specific Genes Regulatory Sequences by MyoD, MRF4 and Myogenin, Nucleic Acids Research, July 2008, Volume 36, (Issue 12), Pages 3916-3925.

R. De Armond, S. Wood et al., Evidence for the Presence of a Guanine Quadruplex Forming Region within a Polypurine Tract of the Hypoxia Inducible Factor 1α Promoter, Biochemistry, December 2005, Volume 44, (Issue 49), Pages 16341-16350.

A. Siddiqui-Jain, C. L. Grand et al., Direct Evidence for a G-quadruplex in a Promoter Region and its Targeting with a Small Molecule to Repress c-MYC Transcription, Proc. Natl. Acad. Sci. USA, September 2002, Volume 99, Pages 11593-11598.

N. Kumar, R. Basundra et al., Elevated Polyamines Induce c-MYC Over-expression by Perturbing Quadruplex-WC Duplex Equilibrium, Nucleic Acids Research, June 2009, Volume 37, (Issue 10), Pages 3321-3331.

A. T. Phan, Y. S. Modi et al., Propeller-Type Parallel-Stranded G-Quadruplexes in the Human c-myc Promoter, Journal of the American Chemical Society, July 2004, Volume 126, (Issue 28), Pages 8710-8716.

A. Ambrus, D. Chen et al., Solution Structure of the Biologically Relevant G-Quadruplex Element in the Human c-MYC Promoter. Implications for G-Quadruplex Stabilization, Biochemistry, February 2005, Volume 44, (Issue 6), Pages 2048-2058.

A. T. Phan, V. Kuryavyi et al., Small-molecule Interaction with a Five-guanine-tract G-quadruplex Structure from the Human MYC promoter, Nat Chem Biol, August 2005, Volume 1, (Issue 3), Pages 167-173.

R. I. Mathad, c-MYC promoter G-quadruplex formed at the 5′-end of NHEIII1 element: insights into biological relevance and parallel-stranded G-quadruplex stability, Nucleic Acids Research, July 2011, Pages 1-11.

M. Webba da Silva, Geometric Formalism for DNA Quadruplex Folding, Chemistry – A European Journal, October 2007, Volume 13, (Issue 35), Pages 9738-9745.

S. Balasubramanian, L. H. Hurley et al., Targeting G-quadruplexes in Gene Promoters: a Novel Anticancer Strategy? , Nat Rev Drug Discov, April 2011, Volume 10, (Issue 4), Pages 261-275.

D. Monchaud and M.-P. Teulade-Fichou, A Hitchhiker's Guide to G-quadruplex Ligands, Organic & Biomolecular Chemistry, February 2008, Volume 6, (Issue 4), Pages 627-636.

R. J. Harrison, J. Cuesta et al., Trisubstituted Acridine Derivatives as Potent and Selective Telomerase Inhibitors, Journal of Medicinal Chemistry, October 2003, Volume 46, (Issue 21), Pages 4463-4476.

H. Han, D. R. Langley et al., Selective Interactions of Cationic Porphyrins with G-Quadruplex Structures, Journal of the American Chemical Society, September 2001, Volume 123, (Issue 37), Pages 8902-8913.

E. De Pauw, L. Guittat et al., Selective Interaction of Ethidium Derivatives with Quadruplexes: An Equilibrium Dialysis and Electrospray Ionization Mass Spectrometry Analysis, Biochemistry, September 2003, Volume 42, (Issue 35), Pages 10361-10371.

G. Breuzard, J.-M. Millot et al., Selective Interactions of Ethidiums with G-Quadruplex DNA Revealed by Surface-Enhanced Raman Scattering, Analytical Chemistry, August 2003, Volume 75, (Issue 16), Pages 4305-4311.

J.-L. Zhou, Y.-J. Lu et al., Synthesis and Evaluation of Quindoline Derivatives as G-Quadruplex Inducing and Stabilizing Ligands and Potential Inhibitors of Telomerase, Journal of Medicinal Chemistry, November 2005, Volume 48, (Issue 23), Pages 7315-7321.

T.-M. Ou, Y.-J. Lu et al., Stabilization of G-Quadruplex DNA and Down-Regulation of Oncogene c-myc by Quindoline Derivatives, Journal of Medicinal Chemistry, April 2007, Volume 50, (Issue 7), Pages 1465-1474.

W.-J. Zhang, T.-M. Ou et al., 9-Substituted Berberine Derivatives as G-quadruplex Stabilizing Ligands in Telomeric DNA, Bioorganic & Medicinal Chemistry, August 2007, Volume 15, (Issue 16), Pages 5493-5501.

M.-Y. Kim, H. Vankayalapati et al., Telomestatin, a Potent Telomerase Inhibitor That Interacts Quite Specifically with the Human Telomeric Intramolecular G-Quadruplex, Journal of the American Chemical Society, March 2002, Volume 124, (Issue 10), Pages 2098-2099.

E. M. Rezler, J. Seenisamy et al., Telomestatin and Diseleno Sapphyrin Bind Selectively to Two Different Forms of the Human Telomeric G-Quadruplex Structure, Journal of the American Chemical Society, July 2005, Volume 127, (Issue 26), Pages 9439-9447.

F. Rosu, V. Gabelica et al., Telomestatin-induced Stabilization of the Human Telomeric DNA Quadruplex Monitored by Electrospray Mass Spectrometry, Chemical Communications, November 2003, (Issue 21), Pages 2702-2703.

Y. Qin, J. S. Fortin et al., Molecular Cloning of the Human Platelet-Derived Growth Factor Receptor β (PDGFR-β) Promoter and Drug Targeting of the G-Quadruplex-Forming Region To Repress PDGFR-β Expression, Biochemistry, May 2010, Volume 49, (Issue 19), Pages 4208-4219.

T. Agarwal, S. Roy et al., Selective Targeting of G-Quadruplex Using Furan-Based Cyclic Homooligopeptides: Effect on c-MYC Expression, Biochemistry, September 2010, Volume 49, (Issue 38), Pages 8388-8397.

T. Agarwal, S. Roy et al., Furan Based Cyclic Homo-oligopeptides Bind G-quadruplex Selectively and Repress c-MYC Transcription, Bioorganic & Medicinal Chemistry Letters, August 2010, Volume 20, (Issue 15), Pages 4346-4349.

D. N. Kaluzhny, A. K. Shchyolkina et al., Novel Indolocarbazole Derivative 12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione is a Preferred c-Myc Guanine Quadruplex Ligand, Journal of Nucleic Acids, November 2011, Volume 2011,.

Y. Ma, T.-M. Ou et al., Quinolino-benzo-[5, 6]-dihydroisoquindolium Compounds Derived from Berberine: A New Class of Highly Selective Ligands for G-quadruplex DNA in c-myc Oncogene, European Journal of Medicinal Chemistry, May 2011, Volume 46, (Issue 5), Pages 1906-1913.

R. Ferreira, R. Artali et al., Acridine and Quindoline Oligomers Linked Through a 4-aminoproline Backbone Prefer G-quadruplex Structures, Biochimica et Biophysica Acta (BBA) - General Subjects, August 2011, Volume 1810, (Issue 8), Pages 769-776.

J. Dash, Z. A. E. Waller et al., Synthesis and Binding Studies of Novel Diethynyl-Pyridine Amides with Genomic Promoter DNA G-Quadruplexes, Chemistry – A European Journal, April 2011, Volume 17, (Issue 16), Pages 4571-4581.

D. Peng, J.-H. Tan et al., Bisaryldiketene Derivatives: A New Class of Selective Ligands for c-myc G-quadruplex DNA, Bioorganic & Medicinal Chemistry, December 2010, Volume 18, (Issue 23), Pages 8235-8242.

K. Suntharalingam, A. J. P. White et al., Two Metals Are Better than One: Investigations on the Interactions between Dinuclear Metal Complexes and Quadruplex DNA, Inorganic Chemistry, September 2010, Volume 49, (Issue 18), Pages 8371-8380.

P. Ragazzon and J. B. Chaires, Use of Competition Dialysis in the Discovery of G-quadruplex Selective Ligands, Methods, December 2007, Volume 43, (Issue 4), Pages 313-323.

Q. Shang, J.-F. Xiang et al., Fishing Potential Antitumor Agents from Natural Plant Extracts Pool by Dialysis and G-quadruplex Recognition, Talanta, July 2011, Volume 85, (Issue 1), Pages 820-823.

E. Largy, F. Hamon et al., Development of a High-throughput G4-FID Assay for Screening and Evaluation of Small Molecules Binding Quadruplex Nucleic Acid Structures, Analytical and Bioanalytical Chemistry, July 2011, Pages 1-9.

P. L. T. Tran, E. Largy et al., Fluorescence Intercalator Displacement Assay for Screening G4 Ligands Towards a Variety of G-quadruplex Structures, Biochimie, May 2011, In Press, Corrected Proof.

A. De Cian, L. Guittat et al., Fluorescence-based Melting Assays for Studying Quadruplex Ligands, Methods, June 2007, Volume 42, (Issue 2), Pages 183-195.

J.-L. Mergny and J.-C. Maurizot, Fluorescence Resonance Energy Transfer as a Probe for G-Quartet Formation by a Telomeric Repeat, ChemBioChem, February 2001, Volume 2, (Issue 2), Pages 124-132.

B. Juskowiak and S. Takenaka, Fluorescence Resonance Energy Transfer in the Studies of Guanine Quadruplexes, Methods in Molecular Biology, 2006, Volume 335, Pages 311-341.

J. E. Redman, S. Ladame et al., Discovery of G-quadruplex Stabilizing Ligands Through Direct ELISA of a One-bead-one-compound Library, Organic & Biomolecular Chemistry, December 2006, Volume 4, (Issue 23), Pages 4364-4369.

D.-L. Ma, D. S.-H. Chan et al., Molecular Modeling of Drug-DNA Interactions: Virtual Screening to Structure-based Design, Biochimie, April 2011, In Press, Corrected Proof.

M. Webba da Silva, NMR Methods for Studying Quadruplex Nucleic acids, Methods, December 2007, Volume 43, (Issue 4), Pages 264-277.

D. S.-H. Chan, H. Yang et al., Structure-based Optimization of FDA-approved Drug Methylene Blue as a c-myc G-quadruplex DNA Stabilizer, Biochimie, June 2011, Volume 93, (Issue 6), Pages 1055-1064.

O. L. Galmarini, I. O. Mastronardi et al., Two Novel Metabolites of Aspergillus fonsecaeus, Cellular and Molecular Life Sciences, June 1974, Volume 30, (Issue 6), Pages 586-586.

H.-M. Lee, D. S.-H. Chan et al., Identification of Natural Product Fonsecin B as a Stabilizing Ligand of c-myc G-quadruplex DNA by High-throughput Virtual Screening, Chemical Communications, July 2010, Volume 46, (Issue 26), Pages 4680-4682.


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