Discovery of an Unexpected Similarity in Ligand Binding between BRD4 and PPARγ

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it especially critical chemical biology to identify further key regulators a disease take advantage polypharmacology effects. Here, we present new concept that combines scaffold-based analysis bioactivity data with subsequent screening novel inhibitors target interest. The initial revealed flavone-like scaffold can be found ligands unrelated indicating similarity ligand binding. This was investigated by testing compounds on bromodomain-containing 4 (BRD4) were similar known other identified targets. Several BRD4 proven validated hits based orthogonal assays X-ray crystallography. most important discovery an unexpected relationship peroxisome-proliferator activated receptor gamma (PPARγ). Both share binding site similarities near common hydrophobic subpocket which should allow design polypharmacology-based targeting both proteins. Such dual-BRD4-PPARγ modulators open up therapeutic opportunities, because are drug targets cancer therapy many more diseases. Thereon, complex structure sulfasalazine obtained involves two bromodomains could potential starting point bivalent inhibitor.