期刊
NATURE REVIEWS DRUG DISCOVERY
卷 16, 期 11, 页码 773-786出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nrd.2017.179
关键词
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资金
- AbbVie
- Bayer Pharma
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute [OGI-055]
- Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD) [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Research, Innovation and Science (MRIS)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- Canadian Institute for Health Research (CIHR) [FRN-125792]
- CIHR [MOP 126129]
- Canadian Cancer Society Research Institute [703906]
- Genome Canada
- Genome Quebec
- National Institutes of Health [R01OD010929]
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 beta-propeller domain-containing protein family. Recently, two WDR domain-containing proteins, WDR5 and EED, as well as other beta-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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