Protein-protein interaction inhibitor discovery has proven difficult due to the large surface area and dynamic interfaces of proteins. To facilitate the early lead discovery rate we have developed a rapid protein-based 19F NMR method for detecting protein-ligand interactions by screening low complexity molecules (fragments) as well as higher complexity molecules. We recently applied this method for the discovery of new small molecules against the epigenetic class of effector domains called bromodomains. I will address the synthesis, development, and application of three of our inhibitors for studying epigenetic protein function. Our efforts towards development of submicromolar pan-inhibitors of the bromodomain-and extra terminal family (BET) of bromdomains will be described first, as well as a domain 1 selective inhibitor of the BET family. Finally, our discovery of a non-BET bromodomain inhibitor for BPTF will be discussed. This inhibitor has helped describe a new role for BPTF regulation of the oncogene, c-Myc and a new interaction with histone variant H2A.Z. The speed, ease of interpretation, and low concentration of protein needed for binding experiments affords a new method to discover and characterize both native and new ligands for bromodomains and may find utility in the study of additional epigenetic “reader” domains.

Applications of protein-observed 19F NMR (PrOF NMR) for inhibitor discovery of BET and non-BET bromodomains

255th National Meeting (2018)

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