Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Aho, Erin R and Wang, Jing and Gogliotti, Rocco D and Howard, Gregory C and Phan, Jason and Acharya, Pankaj and Macdonald, Jonathan D and Cheng, Ken and Lorey, Shelly L and Lu, Bin and Wenzel, Sabine and Foshage, Audra M and Alvarado, Joseph and Wang, Feng and Shaw, J Grace and Zhao, Bin and Weissmiller, April M and Thomas, Lance R and Vakoc, Christopher R and Hall, Matthew D and Hiebert, Scott W and Liu, Qi and Stauffer, Shaun R and Fesik, Stephen W and Tansey, William P (2019) Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity. Cell reports, 26 (11). 2916-2928.e13. ISSN 2211-1247

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.

Item Type: Article
Date Deposited: 28 Mar 2019 00:45
Last Modified: 28 Mar 2019 00:45
URI: https://oak.novartis.com/id/eprint/39351

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.