AI Article Synopsis
- WDR5, a protein associated with chromatin, is a potential target for cancer treatment, focusing on inhibiting a specific area known as the "WIN site."
- Researchers have created effective WIN site inhibitors that demonstrate how WDR5 interacts with chromatin and affects specific gene expressions.
- These inhibitors can remove WDR5 from chromatin, leading to decreased gene expression and potential therapeutic implications for various types of cancer.
Article Abstract
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448596 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2019.02.047 | DOI Listing |
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