Congratulations to Jan Gerhartz for his first publication of a PhD in the Nowak Lab! Jan wrote a perspective article summarizing a new concept of bifunctional small molecules that can dimerize proteins and therefore generate a more potent and selective inhibitors. Small molecule inhibition relies on maintaining high occupancy of the protein target and are frequently limited for potency and selectivity. These types of inhibitors have been recently developed to target an E3 ubiquitin ligase KEAP1. KEAP1, controlled by the redox activity of the cell is known to degrade transcription factor Nrf2. Nrf2 is known for its importance in acute inflammatory conditions where activation has been shown to be protective against immunological challenge. Inhibitors of KEAP1 would result in upregulation of Nrf2 are therefore highly sought after. Jan puts a nice perspective on the novel idea of chemically linking two inhibitors together to form a single bifunctional molecule - strategy recently applied to KEAP1. These strategies could enable generation of molecules with improved selectivity and potency for many dimeric protein substrates.
You can read the full article here:
https://www.sciencedirect.com/science/article/abs/pii/S2451945624002150
