Stabilization of c-KIT G-quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41

Stefania Mazzini, Raimundo Gargallo, Loana Musso, Francesca De Santis, Anna Aviñó, Leonardo Scaglioni, Ramon Eritja, Massimo Di Nicola, Franco Zunino, Annabella Amatulli, Sabrina Dallavalle

Research output: Contribution to journalArticle

Abstract

The stabilization of G-quadruplex DNA structures by small molecules with affinity to oncogene promoters has emerged as a promising anticancer strategy, due to a potential role in gene expression regulation. We explored the ability of BMH-21 (1) and its analogue BA-41 (2) to bind the G-quadruplex structure present in the c-KIT promoter by biophysical methods and molecular modeling. We provide evidence that both compounds interact with the c-KIT 21-mer sequence. The stable monomeric intramolecular parallel G-quadruplex obtained by the mutation of positions 12 and 21 allowed the precise determination of the binding mode by NMR and molecular dynamics studies. Both compounds form a complex characterized by one ligand molecule positioned over the tetrad at the 3-end, stabilized by an extensive network of π–π interactions. The binding constants (Kb) obtained with fluorescence are similar for both complexes (around 106 M−1 ). Compound BA-41 (2) showed significant antiproliferative activity against a human lymphoma cell line, SU-DHL4, known to express substantial levels of c-KIT. However, the partial inhibition of c-KIT expression by Western blot analysis suggested that the interaction of compound 2 with the c-KIT promoter is not the primary event and that multiple effects provide a contribution as determinants of biological activity.

Original languageEnglish
Article number4927
JournalInternational Journal of Molecular Sciences
Volume20
Issue number19
DOIs
Publication statusPublished - Oct 1 2019

Keywords

  • C-KIT
  • CD
  • G-quadruplex
  • NMR spectroscopy
  • Pyridoquinazolinone derivatives

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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    Mazzini, S., Gargallo, R., Musso, L., De Santis, F., Aviñó, A., Scaglioni, L., Eritja, R., Di Nicola, M., Zunino, F., Amatulli, A., & Dallavalle, S. (2019). Stabilization of c-KIT G-quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41. International Journal of Molecular Sciences, 20(19), [4927]. https://doi.org/10.3390/ijms20194927