WD-repeat domain proteins: a novel target class?

Antagonism of protein-protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. However, successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets as opposed to the much more common large, flat protein interaction surfaces. Here we review one of the most abundant PPI domains in the human proteome, the WD40 repeat domain (WDR), which has a central peptide-binding pocket. Recently, two WDR proteins, WDR5 and EED, have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDRs represent a novel target class for drug discovery? While clinical validation remains to be seen, a cautious optimism is justified, considering the ubiquitous involvement of WDR proteins across multiple disease-associated pathways. The druggability and structural diversity of WDR binding pockets suggest that this prevalent domain class could open-up areas of biology that have so far resisted drug discovery efforts.