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G-quadruplex-mediated specific recognition, stabilization and transcriptional repression of bcl-2 by small molecule

Nirali Pandya1, Mamta Singh2, Reshma Rani3

  • 1Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India.

Archives of Biochemistry and Biophysics
|December 13, 2022
PubMed

Insights

A novel small molecule, BiGh, effectively targets the G-quadruplex structure in the bcl-2 oncogene promoter. This G-quadruplex stabilizer demonstrates high affinity and selectivity, offering a promising new avenue for anti-cancer therapeutics.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • The bcl-2 oncogene promotes cancer by inhibiting apoptosis and is overexpressed in many cancers.
  • Targeting the G-quadruplex (G4) structure in the bcl-2 promoter offers a potential therapeutic strategy.
  • Developing selective small molecules for G4 structures remains a challenge.

Purpose of the Study:

  • To identify and characterize a small molecule that selectively binds and stabilizes the bcl-2 G4 structure.
  • To evaluate the anti-cancer potential of the identified molecule through its effect on bcl-2 transcription and apoptosis.

Main Methods:

  • Synthesis and characterization of the small molecule 1,3-bis-(furan-2-yl-methylidene-amino) guanidine (BiGh).
  • Assessment of BiGh binding affinity and selectivity for bcl-2 G4 DNA using biophysical methods.
  • Evaluation of BiGh's effect on bcl-2 transcription, cell cycle, and apoptosis in cancer cells.
  • In silico ADME profiling for drug-likeness prediction.

Main Results:

  • BiGh exhibits very high affinity and selectivity for the bcl-2 G4 DNA structure over other G4s and duplex DNA.
  • BiGh stabilizes the bcl-2 G4 conformation, increasing thermal stability by up to 15°C.
  • BiGh significantly suppresses bcl-2 transcription and translation in cervical cancer cells via a G4-dependent mechanism, inducing cell cycle arrest and apoptosis.
  • In silico analysis suggests BiGh possesses favorable drug-like properties.

Conclusions:

  • BiGh is a potent and selective stabilizer of the bcl-2 G-quadruplex.
  • BiGh downregulates bcl-2 expression and exhibits anti-cancer activity, making it a promising lead compound for therapeutic development.
  • This study provides a foundation for developing G4 stabilizers with drug-like properties for cancer treatment.
Keywords:
ApoptosisBcl-2 DNACancerG-quadruplex DNASmall molecule

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