Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex

David R. Calabrese, Xiang Chen, Elena C. Leon, Snehal M. Gaikwad, Zaw Phyo, William M. Hewitt, Stephanie Alden, Thomas A. Hilimire, Fahu He, Aleksandra M. Michalowski, John K. Simmons, Lindsey B. Saunders, Shuling Zhang, Daniel Connors, Kylie J. Walters (), Beverly A. Mock () and John S. Schneekloth ()
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David R. Calabrese: National Cancer Institute
Xiang Chen: National Cancer Institute
Elena C. Leon: National Cancer Institute
Snehal M. Gaikwad: National Cancer Institute
Zaw Phyo: National Cancer Institute
William M. Hewitt: National Cancer Institute
Stephanie Alden: National Cancer Institute
Thomas A. Hilimire: National Cancer Institute
Fahu He: National Cancer Institute
Aleksandra M. Michalowski: National Cancer Institute
John K. Simmons: National Cancer Institute
Lindsey B. Saunders: National Cancer Institute
Shuling Zhang: National Cancer Institute
Daniel Connors: National Cancer Institute
Kylie J. Walters: National Cancer Institute
Beverly A. Mock: National Cancer Institute
John S. Schneekloth: National Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06315-w

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