Objective

Bromodomain proteins family (BRD) has been rapidly become an attractive epigenetic target for the intervention with small molecules which have been progressed to preclinical and clinical evaluation for treating cancer, inflammation, and neurological disorders. In order to explore this highly druggable class of therapeutic targets, we developed new fragment-driven approach for effective search of novel hits with extremely fast qualitative hit expansion and follow-up opportunities. Fragment-based drug discovery approach in combination with ligand observed ¹⁹F-NMR screening techniques were applied to find new small molecule inhibitors of the BRD4. The set of fluorine fragments was designed to be a unique tool for multipurpose FBDD projects. The algorithm of effective fragment screening and verification of actives has been developed and successfully implemented within the general scheme described below. Two fragment hit series have been explored for analogs synthesis and SAR development.