Berberine Molecular Recognition of the Parallel MYC G-Quadruplex in Solution

Dickerhoff, Jonathan; Brundridge, Nicole M.; McLuckey, Scott A.; Yang, Danzhou

doi:10.1021/acs.jmedchem.1c01508

Cited by 27 publications

(22 citation statements)

References 45 publications

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“…Our ligand complex structures demonstrate the importance of the shape of the ligand and the two flanking sequences in determining the binding specificity of Myc121. 25,26,28,29 Base recruitment is likely to be the key step for ligand recognition. Intriguingly, our systematic analysis of the four available NMR structures with Myc121 revealed that the flanking base is recruited in a conserved residue-specific way (Figure 9B).…”

Section: G-quadruplexesmentioning

confidence: 99%

“…Our laboratory has been fascinated by G-quadruplex structures and functions and started this exciting journey in 2002 to study the biologically relevant intramolecular G-quadruplexes formed in human telomeres and oncogene promoters. − In 2005 and 2006, we described the potassium solution structures of the G-quadruplexes formed in the c-Myc oncogene promoter and in human telomeres. , Since then, we have described the potassium solution structures and functions of G-quadruplexes formed in several other oncogene promoters, such as BCL2, VEGF, and PDGFR-β. − Toward G-quadruplex-targeted small molecules, we have characterized the recognition of biologically relevant human telomeric G-quadruplexes and promoter G-quadruplexes, particularly c-Myc. ,,,− One of our primary approaches, high-field nuclear magnetic resonance (NMR) spectroscopy, represents a major method for the determination of high-resolution G-quadruplex structures under physiologically relevant solution conditions.…”

Section: Introductionmentioning

confidence: 99%

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DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting

et al. 2022

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Metrics & MoreArticle RecommendationsCONSPECTUS: 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-β, 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-β 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-β 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-β promoter. Moreover, w...

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Section: G-quadruplexesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting

et al. 2022

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“…Most of these compounds have a planar aromatic ring system that can stabilize G4s. Several plant secondary metabolites (PSMs) have been shown to share this feature and bind G4s: fisetin, sanguinarine, thymoquinone, quercetin, and berberine [ 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of G-Quadruplex-Binding Plant Secondary Metabolites on c-MYC Expression

Zenkov

Кирсанов

Ogloblina

et al. 2022

IJMS

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Guanine-rich DNA sequences tending to adopt noncanonical G-quadruplex (G4) structures are over-represented in promoter regions of oncogenes. Ligands recognizing G4 were shown to stabilize these DNA structures and drive their formation regulating expression of corresponding genes. We studied the interaction of several plant secondary metabolites (PSMs) with G4s and their effects on gene expression in a cellular context. The binding of PSMs with G4s formed by the sequences of well-studied oncogene promoters and telomeric repeats was evaluated using a fluorescent indicator displacement assay. c-MYC G4 folding topology and thermal stability, as well as the PMS influence on these parameters, were demonstrated by UV-spectroscopy and circular dichroism. The effects of promising PSMs on c-MYC expression were assessed using luciferase reporter assay and qPR-PCR in cancer and immortalized cultured cells. The ability of PMS to multi-targeting cell signaling pathways was analyzed by the pathway-focused gene expression profiling with qRT-PCR. The multi-target activity of a number of PSMs was demonstrated by their interaction with a set of G4s mimicking those formed in the human genome. We have shown a direct G4-mediated down regulation of c-MYC expression by sanguinarine, quercetin, kaempferol, and thymoquinone; these effects being modulated by PSM’s indirect influence via cell signaling pathways.

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“…The loop and groove regions exhibited the most essential difference among the different G4s. 65 Thus, improving the selective binding of 19a to the c-MYC G4 might be related to this binding mode. 57,66 Because the loop structure is the essential binding site for NM23-H2 and BLM, the significant increase in 19a in disrupting protein/G4 interactions might result from this binding site being blocked.…”

Section: Interactions Between 19a and C-myc G4mentioning

confidence: 99%

Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex

Yuan

et al. 2022

J. Med. Chem.

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c-MYC is a key driver of tumorigenesis. Repressing the transcription of c-MYC by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed c-MYC G4 ligand 1. Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-MYC G4 binding, stabilization, and protein binding disruption abilities than 1. Our further evaluation indicated that 19a blocked c-MYC transcription by targeting the promoter G4, leading to c-MYC-dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-MYC downregulation. Notably, the safety of 19a was dramatically improved compared to 1. Our findings indicated that 19a could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.

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Berberine Molecular Recognition of the Parallel MYC G-Quadruplex in Solution

Cited by 27 publications

References 45 publications

DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting

DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting

Effects of G-Quadruplex-Binding Plant Secondary Metabolites on c-MYC Expression

Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex

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