Title
Targeting a noncanonical, hairpin-containing G-quadruplex structure from the MYCN gene
Author
Mo Yang, Sakereh Carter, Shaifaly Parmar, Desta D. Bume, David R. Calabrese, Xiao Liang, Kamyar Yazdani, Man Xu, Zhihui Liu, Carol J. Thiele and John S. Schneekloth, Jr
Year
2021
Journal
Nucleic Acids Research ,Volume 49, Issue 14, 20 August 2021, Pages 7856–7869
Abstract
The MYCN gene encodes the transcription factor N-Myc, a driver of neuroblastoma (NB). Targeting G-quadruplexes (G4s) with small molecules is attractive strategy to control the expression of undruggable proteins such as N-Myc. However, selective binders to G4s are challenging to identify due to the structural similarity of many G4s. Here, we report the discovery of a small molecule ligand (4) that targets the noncanonical, hairpin containing G4 structure found in the MYCN gene using small molecule microarrays (SMMs). Unlike many G4 binders, the compound was found to bind to a pocket at the base of the hairpin region of the MYCN G4. This compound stabilizes the G4 and has affinity of 3.5 ± 1.6 μM. Moreover, an improved analog, MY-8, suppressed levels of both MYCN and MYCNOS (a lncRNA embedded within the MYCN gene) in NBEB neuroblastoma cells. This work indicates that the approach of targeting complex, hybrid G4 structures that exist throughout the human genome may be an applicable strategy to achieve selectivity for targeting disease-relevant genes including protein coding (MYCN) as well as non-coding (MYCNOS) gene products.
Instrument
J-1500
Keywords
Circular dichroism, MYCN gene, G-quadruplex, small molecule microarrays