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Nat Rev Drug Discov. 2017 Nov;16(11):773-786. doi: 10.1038/nrd.2017.179. Epub 2017 Oct 13.

WD40 repeat domain proteins: a novel target class?

Author information

Structural Genomics Consortium, University of Toronto, Toronto, 101 College St, MaRS South Tower, Suite 700, Ontario M5G 1L7, Canada.
Department of Pharmacology and Toxicology, Medical Science Building, Room 4207, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Institute for Research in Immunology and Cancer, Université de Montréal, Pavillon Marcelle-Coutu, 2950 Chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
The Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Discovery Research, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, USA.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.


Antagonism of protein-protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. Successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets rather than the more common large, flat protein interaction surfaces. Here, we review one of the most abundant PPI domains in the human proteome, the WD40 repeat (WDR) domain, which has a central peptide-binding pocket and is a member of the β-propeller domain-containing protein family. Recently, two WDR domain-containing proteins, WDR5 and EED, as well as other β-propeller domains have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDR domains be a novel target class for drug discovery? Although the research is at an early stage and therefore not clinically validated, cautious optimism is justified, as WDR domain-containing proteins are involved in multiple disease-associated pathways. The druggability and structural diversity of WDR domain binding pockets suggest that understanding how to target this prevalent domain class will open up areas of disease biology that have so far resisted drug discovery efforts.

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