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NIH Research Festival

September 16 – 18, 2015

Selective small molecule stabilization of G-quadruplex drives transcriptional regulation of MYC

Thursday, September 17, 2015 – Poster Session II
12:00 – 1:30 p.m.

FAES Terrace

NCI

CANCER-17

Authors

  • EC Leon
  • KM Felsenstein
  • LB Saunders
  • JK Simmons
  • S Zhang
  • A Michalowski
  • P Gareiss
  • BA Mock
  • JS Schneekloth

Abstract

The transcription factor MYC plays an integral role in cell cycle progression, differentiation, angiogenesis, and cellular maintenance. Its dysregulation is common in many types of cancer and leads to increased tumorigenesis. One method of small molecule inhibition of MYC is to selectively stabilize the G-quadruplex (G4) present in the nuclease hypersensitive element III (NHE III) in its promoter, which accounts for 85% of MYC expression. However, one challenge to overcome with this technique is the identification of small molecules that specifically modulate one of many G4-driven genes. Using a small molecule microarray screen, we first identified one hit compound that both selectively, and reversibly, stabilizes MYC G4 DNA to inhibit MYC expression. Surface plasmon resonance (SPR) and thermal melt assays demonstrated the reversibility of binding, as well as established the compound’s single digit micromolar affinity. Confirming a G4-dependent mechanism of action, the compound induced selective toxicity in multiple myeloma cell lines containing a G4 in the MYC promoter, while demonstrating minimal effects in peripheral blood mononucleocytes and in a Burkitt’s lymphoma cell line that lacks a G4 in the MYC promoter. Furthermore, we found dose-dependent inhibition of PCR product formation in an in vitro PCR-stop assay. Gene expression analysis validated that the hit compound selectively inhibits MYC and other MYC effectors more so than other G4 containing genes, such as VEGFA, KRAS, and RB1. Our data illustrates small molecule stabilization of MYC’s G-quadruplex as a means for decreasing oncogenic MYC expression.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021

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