Chemical Epigenetics Approaches for Developing Selective Inhibitors and Degraders of Bromodomain-Containing Proteins

Fluorine is the thirteenth most abundant element in the earth’s crust and most abundant halogen, but is largely absent from nature’s most essential biopolymers and natural products.  Despite this absence in biology, organofluorine compounds hold significant promise for impacting human health, including for imaging applications (¹⁸F PET and ¹⁹F MRI), structural biology, drug screening, and drug development. As one innovation in our lab, we develop protein-observed ¹⁹F NMR (PrOF NMR) approaches using ¹⁹F-labeled side-chains that are enriched at protein-protein-interaction interfaces. We use PrOF NMR for characterizing protein-protein and nucleic acid interactions and drug discovery applications.  

Today, I will discuss one recent medicinal chemistry application of PrOF NMR, which has led to potent inhibitors and the selective degraders (PROTACs) of the epigenetic regulatory protein BRD4 in the first part of the talk and the Bromodomain PHD Finger Transcription Factor, BPTF in the second part. These proteins are emerging drug targets for developing anticancer and anti-inflammatory agents.  For BPTF, despite a druggable bromodomain which engages in protein-protein interactions with acetylated histones, small molecule discovery is at an early stage. Our lab has developed novel screening approaches using PrOF NMR, protein crystallography, and supporting biophysical methods to develop both the first inhibitor of the BPTF bromodomain, and now more potent and selective chemical probes. These molecules have been used in both cell-based assays and in vivo. They have demonstrated the importance of the bromodomain for mediating transcription as well as serving as a mechanism for reducing MYC and MYCN expression. Most recently they have showed synergistic effects with chemotherapeutic drugs in breast cancer models. Finally, their potential as novel heterobifunctional molecules and new PHD inhibitors will be discussed.  These new inhibitors and degrader are envisioned to serve as useful chemical probes of BPTF function both in normal and pathophysiology.