Environmental cues regulate many biological processes, coordinating cellular pathways to respond to changing conditions. Such regulation is often initiated by sensory protein domains which expand their chemical repertoire by using small molecule ligands to convert environmentally-triggered changes into altered protein/protein interactions. Several families of these domains have evolved with remarkable diversity in their inputs and outputs. Using a combination of biophysics, biochemistry and synthetic chemistry, we seek to gain insight into the mechanistic controls of such environmental sensing domains for both fundamental understanding and subsequent artificial control.
Here I will discuss examples of our work showing how such signaling proteins can be targeted for small molecule therapeutics, emphasizing the roles of solution NMR spectroscopy at various stages of the discovery process. I will use Merck’s newly-approved belzutifan – a novel anti-cancer therapeutic targeting the Hypoxia Inducible Factor 2 (HIF-2) transcription factor – as the centerpiece of this discussion. This compound arose from academic studies in my group through subsequent development at a startup company, Peloton Therapeutics, providing numerous examples from library screening to in-depth studies of protein/ligand interactions that demonstrate the versatility of NMR-driven approaches in the development of an artificial regulator of a biomedically-critical protein/protein interaction. Future directions stemming from this work will also be discussed.