Discovery of new small molecule inhibitors of the BPTF bromodomain

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Chromatin remodeling is essential for cellular processes including gene transcription and DNA repair.
• The Bromodomain PHD finger Transcription factor (BPTF) is the largest subunit of the Nucleosome Remodeling Factor (NURF) complex and is implicated in cancer.
• Developing BPTF bromodomain inhibitors is a current challenge in cancer therapy.

Purpose of the Study:

• To identify novel inhibitors of the BPTF bromodomain.
• To characterize the inhibitory potential and mechanism of identified compounds.
• To evaluate the anti-cancer effects of lead compounds in relevant cell lines.

Main Methods:

• Homogenous Time-Resolved Fluorescence Resonance Energy Transfer (HTRF) assay for inhibitor screening.
• Biochemical analysis to determine binding affinity.
• Molecular docking simulations to predict binding modes.
• Cell-based assays to assess anti-proliferative effects and target gene expression.

Main Results:

• Sanguinarine chloride was identified as a novel BPTF inhibitor with an IC50 of 344.2 ± 25.1 nM.
• Biochemical assays confirmed high binding affinity of Sanguinarine chloride to the BPTF bromodomain.
• Molecular docking provided insights into the binding mode and guided derivative design.
• Sanguinarine chloride demonstrated significant anti-proliferative activity in MIAPaCa-2 cells and inhibited c-Myc expression.

Conclusions:

• Sanguinarine chloride is a promising scaffold for developing potent BPTF bromodomain inhibitors.
• The compound exhibits anti-cancer properties by targeting BPTF and its downstream pathways.
• Further development of Sanguinarine chloride derivatives could lead to new cancer therapeutics.