Bisindolylmaleimide Ligands Stabilize c-MYC G-Quadruplex DNA Structure and Downregulate Gene Expression.
Satendra KumarRajesh Kumar Reddy SannapureddiChaitra S TodankarR RamanathanAnnyesha BiswasBharathwaj SathyamoorthyPushpangadan I PradeepkumarPublished in: Biochemistry (2022)
G-Quadruplex (G4) structures play a pivotal role in diverse biological functions, including essential processes, such as telomere maintenance and gene regulation. G4 structures formed in functional regions of genomes are actively pursued toward therapeutics and are targeted by small-molecule ligands that alter their structure and/or stability. Herein, we report the synthesis of bisindolylmaleimide-based ( BIM ) ligands, which preferentially stabilize parallel G4 structures of c-MYC and c-KIT oncogenes over the telomeric h-RAS1 G4 and duplex DNAs. The preferential stabilization of parallel G4s with BIM ligands is further validated by the DNA polymerase stop assay, where stop products were only observed for templates containing the c-MYC G4 sequence. Nuclear magnetic resonance (NMR) titration studies indicate that the lead ligand BIM-Pr1 forms a 2:1 complex with c-MYC G4 DNA with a K D of 38 ± 5 μM. The BIM ligand stacks at the 5' and 3' quartets, with molecular modeling and dynamics studies supporting the proposed binding mode. The ligand is cytotoxic to HeLa cells and downregulates c-MYC gene expression. Collectively, the results present bisindolylmaleimide scaffolds as novel and powerful G4 targeting agents.
Keyphrases
- gene expression
- magnetic resonance
- small molecule
- circulating tumor
- high resolution
- cell free
- single molecule
- dna methylation
- cancer therapy
- cell cycle arrest
- induced apoptosis
- case control
- nucleic acid
- high throughput
- circulating tumor cells
- magnetic resonance imaging
- mass spectrometry
- computed tomography
- signaling pathway
- transcription factor
- tissue engineering
- binding protein
- endoplasmic reticulum stress
- amino acid
- anti inflammatory