Journal
ACCOUNTS OF CHEMICAL RESEARCH
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.accounts.2c00337
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Funding
- National Institutes of Health [R01GM083117, R01CA122952, S10 RR16659, K01CA83886, P30CA023168, R01CA177585, U01CA240346, R01 CA153821]
- Joint International Research by Japan Society for the Promotion of Science [15KK0179]
- Deutsche Forschungsgemeinschaft [427347592]
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DNA G-quadruplexes formed in human telomeres and oncogene promoters are functionally important and have emerged as a promising class of cancer-specific drug targets. In this article, the authors discuss their efforts to understand the structures and functions of these DNA G-quadruplexes and their interactions with small molecules. They have determined the high-resolution structures of telomeric G-quadruplexes and studied G-quadruplexes formed in key oncogene promoters. The authors also highlight the potential of G-quadruplexes as selectively targetable drug receptors and discuss their recent discoveries of small molecules that specifically recognize these G-quadruplexes. Overall, this work provides a strong foundation for future research on G-quadruplexes and the design of G-quadruplex-targeted drugs.
CONSPECTUS: DNA G-quadruplex secondary structures formed in guanine-rich human telomeres and oncogene promoters are functionally important and have emerged as a promising new class of cancer-specific drug targets. These globular intramolecular structures are stabilized by K(+ )or Na+ and form readily under physiological solution conditions. Moreover, G-quadruplexes are epigenetic features and can alter chromatin structure and function together with interactive proteins. Here, we discuss our efforts over the last two decades to understand the structures and functions of DNA G-quadruplexes formed in key oncogene promoters and human telomeres and their interactions with small molecules. Using high-field NMR spectroscopy, we determined the high-resolution structures of physiologically relevant telomeric G-quadruplexes in K+ solution with a major form (hybrid-2) and a minor form (hybrid-1), as well as a two-tetrad intermediate. The intrinsic structural polymorphism of telomeric DNA may be important for the biology of human telomeres, and we proposed a model for the interconversion. More recently, we have worked on G-quadruplexes of MYC, BCL2, PDGFR-beta, VEGF, and k-RAS oncogene promoters. We determined the structure of the major G-quadruplex formed in the MYC promoter, a prototype for parallel G-quadruplexes. It is the first example of the parallel-stranded G(3)NG(3) structure motif with a 1-nt loop, which is prevalent in promoter sequences and likely evolutionarily selected to initiate folding. Remarkably, the parallel MYC promoter G-quadruplexes are highly stable. Additionally, we determined the molecular structures of G-quadruplexes formed in human BCL2, VEGF, and PDGFR-beta promoters, each adopting a unique structure. For example, the BCL2 promoter contains distinct interchangeable G-quadruplexes in two adjacent regions, suggesting precise regulation by different proteins. The PDGFR-beta promoter adopts unique broken-strand and vacancy G-quadruplexes, which can be recognized by cellular guanine metabolites for a potential regulatory role. Structural information on G-quadruplexes in complex with small-molecules is critical for understanding specific recognition and structure-based rational drug design. Our studies show that many G-quadruplexes contain unique structural features such as capping and loop structures, allowing specific recognition by drugs and protein. This represents a paradigm shift in understanding DNA as a drug target: Rather than a uniform, nonselective binding site in duplex DNA, the G-quadruplex is being pursued as a new class of selectively targetable drug receptors. We focus on targeting the biologically relevant MYC promoter G-quadruplex (MycG4) with small molecules and have determined its first and additional drug complex structures. Very recently, we have discovered clinically tested indenoisoquinolines as strong MycG4 binders and potent MYC inhibitors. We have also discovered drugs targeting the unique dGMP-bound-vG4 formed in the PDGFR-beta promoter. Moreover, we determined the complex structures of the first small molecules that specifically recognize the physiologically relevant human telomeric G-quadruplexes. Unlike the previously recognized dogma that the optimal G-quadruplex ligands are large aromatic or cyclic compounds, our results suggest that smaller asymmetric compounds with appropriate functional groups are better choices to specifically bind G-quadruplexes. This body of work lays a strong foundation for future work aimed at understanding the cellular functions of G-quadruplexes and G-quadruplex-targeted drug design.
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