Abstract 3840: High-resolution structural insights into targeting the MYC oncogene G-quadruplex with the quinoline derivative PEQ
Authors: Dickerhoff Jonathan , Dai Jixun , Yang Danzhou 
Published: April 2023

Abstract
The transcription of the MYC oncogene, a central player of oncogenesis, is strongly controlled by DNA G-quadruplexes in its promoter region (MycG4). Stabilization of MycG4 with small molecules downregulates MYC expression and has devastating effects on many cancers. Thus, targeting MycG4 is an attractive anti-cancer strategy especially since the MYC protein is considered a very difficult target. DNA G-quadruplexes are four-stranded secondary structures and enriched in promoters of oncogenes. Their globular shape and high structural diversity distinguishes them from the thread-like and uniform DNA duplex ubiquitously found in the cell. High-resolution structures reveal the molecular interactions between ligands and G-quadruplexes and are the key for structure-based rational design of new and improved drugs. Here, we present the new MycG4 binder PEQ, a quinoline derivative, and describe its molecular recognition of the MycG4. PEQ is more drug-like than many prominent G-quadruplex binder because it lacks an extensive aromatic moiety. Most of the reported G-quadruplex binding ligands include extended and rigid aromatic moieties with less drug-like properties. We used solution NMR and molecular dynamics calculations to first determine the high-resolution structures of the unbound wild-type MycG4, and next structures of PEQ in complex to wild-type MycG4 or the most commonly studied modified MycG4. This modified MycG4 sequence bears a mutated residue in the binding pocket that is critical for ligand interactions. PEQ binds the MycG4 with a 2:1 stoichiometry and stacks on the G-quadruplex ends. Specific binding pockets are formed in which a flanking residue is recruited by the PEQ to form a joint-plane. The identity of the recruited residue controls the orientation of the ligand and the resulting interactions, as shown by structural comparison of PEQ in complex with either the wild-type or mutated MycG4. Including the PEQ structure, four ligand-MycG4 complexes are now available and we performed the first systematic analysis. We show that despite the dynamic character of the flanking sequences, all ligands recruit DNA bases in a conserved and sequence-specific manner. Moreover, we propose the design of complementary hydrogen bonds to match the recruited DNA base with a drug via structure-based rational design. In conclusion, our work introduces the quinoline PEQ as new lead compound for cancer therapeutics targeting MYC through the MycG4. We present the MycG4-ligand structure with wild-type binding sites as more accurate target and identify important aspects of ligand binding to guide future design of cancer therapeutics.
Citation Format: Jonathan Dickerhoff, Jixun Dai, Danzhou Yang. High-resolution structural insights into targeting the MYC oncogene G-quadruplex with the quinoline derivative PEQ. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3840.