Selective chemical intervention on protein-protein interactions: from inhibitors to degraders

Targeting protein-protein interactions (PPIs) is a frontier goal of chemical intervention into biology, and provides attractive new targets for drug discovery. Finding high-quality small molecules targeting PPI sites is, however, a challenging task, and even more so achieving single-target selectivity, especially when the target shares homologous functional domains and highly conserved binding sites with neighboring proteins.
 
Our lab has developed and applied chemical biology approaches, leveraging rational structure-driven medicinal chemistry, to help to address these challenges. Representative examples of our approaches will be illustrated:
1) structure-guided fragment-based design of VH298, a potent, selective and on-target inhibitor of the von Hippel-Lindau (VHL) E3 ubiquitin ligase, providing a novel chemical probe for hypoxia signaling pathway [1,2];
2) development of a chemical genetic approach to allele-selective inhibition of BET bromodomain proteins Brd2, Brd3, Brd4 and BrdT, starting from pan-selective inhibitors such as JQ1 / I-BET762 [3];
3) how we have combined the two inhibitors to design bivalent chemical degraders, also known as PROTACs, which led to the discovery of MZ1, a potent and selective VHL-based degrader of the BET protein Brd4 [4]. Structural insights into PROTAC-induced PPIs between ligase and bromodomain has shone new light into cooperative molecular recognition of bivalent degraders for selective protein degradation, and informed the structure-guided design of highly preferential Brd4 degraders [5].
 
Our work has revealed new selective chemical tools to probe biology (available at the Chemical Probes Portal, www.chemicalprobes.org) and unveiled deeper understanding of how PROTACs work that is impacting their translation from mere chemical tools to future molecular therapeutics.