TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.
Journal article
2016-02-25T00:00:00+00:00
59
1642 - 1647
5
Adaptor Proteins, Signal Transducing, Benzimidazoles, Carrier Proteins, Cell Line, Tumor, Crystallography, X-Ray, DNA-Binding Proteins, Humans, Lysine, Models, Molecular, Molecular Docking Simulation, Nuclear Proteins, Protein Structure, Tertiary, Bromodomain Containing Proteins