Abstract
G-quadruplexes (G4s) are noncanonical DNA structures that frequently occur in the promoter regions of oncogenes, such as MYC, and regulate gene expression. Although G4s are attractive therapeutic targets, ligands capable of discriminating between different G4 structures are rare. Here, we describe DC-34, a small molecule that potently downregulates MYC transcription in cancer cells by a G4-dependent mechanism. Inhibition by DC-34 is significantly greater for MYC than other G4-driven genes. We use chemical, biophysical, biological, and structural studies to demonstrate a molecular rationale for the recognition of the MYC G4. We solve the structure of the MYC G4 in complex with DC-34 by NMR spectroscopy and illustrate specific contacts responsible for affinity and selectivity. Modification of DC-34 reveals features required for G4 affinity, biological activity, and validates the derived NMR structure. This work advances the design of quadruplex-interacting small molecules to control gene expression in therapeutic areas such as cancer.
Highlights
G-quadruplexes (G4s) are noncanonical DNA structures that frequently occur in the promoter regions of oncogenes, such as MYC, and regulate gene expression
We report the discovery of a drug-like compound with dramatic effects on MYC expression in multiple myeloma cells, demonstrate that it acts by a G4-dependent mechanism of action, and solve a complete structure by NMR of the compound in complex with the MYC G4
With DC-34, the most potent compound, MYC protein expression was reduced to 0.4% at a 10 μM dose compared to 50% for the methyl-substituted compound and an increase in potency was observed in the cell viability assay
Summary
G-quadruplexes (G4s) are noncanonical DNA structures that frequently occur in the promoter regions of oncogenes, such as MYC, and regulate gene expression. Small molecules that bind and stabilize the MYC G4 have been shown to decrease MYC expression and present a potential method for targeting cancers where MYC contributes to the oncogenic phenotype[3,4]. Many of these ligands that silence MYC expression in cells are not selective, and their activity cannot always be attributed to a MYC-dependent mechanism of action[24]. We report the discovery of a drug-like compound with dramatic effects on MYC expression in multiple myeloma cells, demonstrate that it acts by a G4-dependent mechanism of action, and solve a complete structure by NMR of the compound in complex with the MYC G4. Insights gained from this structure and the corresponding chemical derivatives provide a basis for the recognition of the MYC G4 and have implications for the development of selective nucleic acidbinding compounds with biological activity
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