The four oncogenes, c-MYC, bcl-2, VEGF, and HIF-1a, all contain polyG/polyC tracts in their promoter regions critical for transcriptional activation. The occurrence of DNA G-quadruplex secondary structures has been demonstrated in the promoter regions of these four oncogenes and has been shown to be a transcriptional modulator. While the DNA G-quadruplexes are promising new drug targets, the evaluation of their potential as cancer therapeutic targets depends on the understanding of biologically relevant G-quadruplex structures. Our preliminary studies have allowed us to identify the predominant forms of G-quadruplexes in the promoter regions of c-MYC, bcl-2, VEGF, and HIF-1a, which appear to represent three different basic G-quadruplex structures with VEGF/HIF-1a G-quadruplexes being the same basic type. The different molecular structures of the promoter G-quadruplexes make these structures attractive targets for pathway-specific drug design. In this proposal we intend to define the specific molecular structure of each G-quadruplex and its drug-complex(es). The structural information obtained will be correlated with the biological data to understand the effective gene modulation. Insight into the structures of the promoter G-quadruplexes and their drug complexes will provide an important basis for structure-based rational drug design. We will test our hypothesis that each promoter G-quadruplex can be specifically targeted by different small molecule drug compounds. In addition to the principle that selectivity can be achieved by interactions with different G-quadruplex core structures, we expect that selectivity can also be achieved by interactions within the external loops and capping structures in which binding pockets are generated. Proof of principle will be important in this regard. We will use a combination of NMR, CD, molecular modeling, and microcalorimetry data in concert with appropriate mutant promoter elements. Our primary approach, high field NMR spectroscopy, represents a major tool for structure determination of biologically relevant G-quadruplexes, due to the difficulty of crystallization of such structures. Our ultimate objective is to use a structure-based approach to rationally design small molecule G-quadruplex-interactive compounds that specifically target the G-quadruplex structure unique to each promoter and modulate gene transcription. Specifically, we plan to 1) determine the molecular structure of the biologically relevant G-quadruplex formed in the promoter region of c-MYC and its drug interactions; 2) determine the molecular structure of the biologically relevant G-quadruplex formed in the promoter region of bcl-2 and its drug interactions; and 3) determine the molecular structure of the biologically relevant G-quadruplex formed in the promoter region of VEGF/HIF-1a and its drug interactions. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA122952-01A1
Application #
7319095
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Knowlton, John R
Project Start
2007-09-03
Project End
2010-07-31
Budget Start
2007-09-03
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$284,654
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Onel, Buket; Carver, Megan; Agrawal, Prashansa et al. (2018) The 3'-end region of the human PDGFR-? core promoter nuclease hypersensitive element forms a mixture of two unique end-insertion G-quadruplexes. Biochim Biophys Acta Gen Subj 1862:846-854
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Brown, Robert V; Wang, Ting; Chappeta, Venkateshwar Reddy et al. (2017) The Consequences of Overlapping G-Quadruplexes and i-Motifs in the Platelet-Derived Growth Factor Receptor ? Core Promoter Nuclease Hypersensitive Element Can Explain the Unexpected Effects of Mutations and Provide Opportunities for Selective Targeting of J Am Chem Soc 139:7456-7475
Deng, Nanjie; Wickstrom, Lauren; Cieplak, Piotr et al. (2017) Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment. J Phys Chem B 121:10484-10497
Wang, Kai-Bo; Li, Da-Hong; Bao, Yu et al. (2017) Structurally Diverse Alkaloids from the Seeds of Peganum harmala. J Nat Prod 80:551-559
Liu, Xiao; Ishizuka, Takumi; Bao, Hong-Liang et al. (2017) Structure-Dependent Binding of hnRNPA1 to Telomere RNA. J Am Chem Soc 139:7533-7539
Lin, Clement; Yang, Danzhou (2017) Human Telomeric G-Quadruplex Structures and G-Quadruplex-Interactive Compounds. Methods Mol Biol 1587:171-196
Onel, Buket; Carver, Megan; Wu, Guanhui et al. (2016) A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription. J Am Chem Soc 138:2563-70
Lin, Clement; Yang, Danzhou (2015) DNA Recognition by a Novel Bis-Intercalator, Potent Anticancer Drug XR5944. Curr Top Med Chem 15:1385-97

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