Aho, Erin R.Weissmiller, April M.Fesik, Stephen W.Tansey, William P.2020-04-172020-04-172019-07-18Aho E.R., Weissmiller A.M., Fesik S.W., Tansey W.P.. Targeting WDR5: A WINning Anti-Cancer strategy. Epigenet Insights. 2019; 12:25168657198652822516-8657http://hdl.handle.net/1803/9927WDR5 is a component of multiple epigenetic regulatory complexes, including the mixed lineage leukemia (MLL)/SET complexes that deposit histone H3 lysine 4 methylation. Inhibitors of an arginine-binding cavity in WDR5, known as the WDR5-interaction (WIN) site, have been proposed to selectively kill MLL-rearranged malignancies via an epigenetic mechanism. We discovered potent WIN site inhibitors and found that they kill MLL cancer cells not through changes in histone methylation. but by displacing WDR5 from chromatin at protein synthesis genes, choking the translational capacity of these cells, and inducing death via a nucleolar stress response. The mechanism of action of WIN site inhibitors reveals new aspects of WDR5 function and forecasts broad therapeutic utility as anti-cancer agents.en-USCreative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Cancer therapychromatinepigenetic mechanismshistone methylationMYCsmall molecule inhibitorsWDR5Article10.1177/2516865719865282