Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.

The chromatin-associated protein WDR5is 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 WDR5target 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 WDR5to chromatinat a small cohort of loci, including a specific subset of ribosome proteingenes. WIN site inhibitors rapidly displace WDR5from chromatinand decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5engages chromatinand forecast that WIN site blockade could have utility against multiple cancer types. © 2019 The Author(s) WDR5is a chromatin-associated protein and promising anti-cancer target. Aho et al. show that WDR5controls the expression of ribosome proteingenes and describe how small molecule inhibitors of WDR5displace it from chromatin, causing impeded translation, nucleolar stress, and induction of p53-dependent apoptosis in leukemia cells. © 2019 The Author(s)