Chemical and Structural Studies Provide a Mechanistic Basis for Selective Recognition of the MYC G-Quadruplex

Authors

• DR Calabrese
• X Chen
• E Leon
• S Gaikwad
• Z Phyo
• WM Hewitt
• S Alden
• TA Hilimire
• F He
• A Michalowski
• JK Simmons
• LB Saunders
• S Zhang
• D Conners
• KJ Walters
• BA Mock
• JS Schneekloth

Abstract

Developing small molecules that bind to and alter the function of regulatory nucleic acid sequences is particularly attractive when they govern the expression of so-called “undruggable” proteins, such as MYC. The MYC gene encodes for the transcription factor MYC, which is regulates a large number of genes in the human genome and has been linked to proliferation, differentiation, apoptosis, and oncogenesis. We synthesized a focused library of analogs, which were evaluated for affinity, ability to silence MYC, and limit cell growth in a MYC-driven multiple myeloma cell line. The most potent analog (DC-34) inhibits MYC at the transcriptional level only when a G4 is present in the promoter. Importantly, DC-34 does not transcriptionally downregulate several other G4-dependent genes to the same extent. To establish a structural basis for selectivity, we synthesized an isotopically labeled DC-34, which was used to solve the NMR structure of DC-34 in complex with the G4. DC-34 adopts a three-dimensional conformation that enables specific contacts with the G4 that govern selectivity and biological activity. Insights gained from this structure and the corresponding chemical derivatives provide a basis for the selective recognition of the MYC G4 and have implications for the development of selective nucleic acid-binding compounds with biological activity. Our work demonstrates that drug-like compounds can discriminate between different G4s by making discrete interactions or altering the conformation of the tail, loop, and tetrad portions of the G4.

Scientific Focus Area: Chemical Biology

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