Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the study of rac-1 are reported, specifically, identification of the active enantiomer for binding to the bromodomain, and reduction in off-target binding to known kinase targets. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the methods for selectivity, ligand deconstruction, and affinity determination. To enable future analysis of biological activity, cell activity in a panel of cancer cell lines was carried out using CRISPR-Cas9 and (S)-1 to evaluate cell-based model systems that are sensitive to BPTF inhibition.

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