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

Journal Article · Fri Mar 01 00:00:00 EST 2019 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2019.02.047· OSTI ID:1547648

Aho, Erin R.; Wang, Jing; Gogliotti, Rocco D.; Howard, Gregory C.; Phan, Jason; Acharya, Pankaj; Macdonald, Jonathan D.; Cheng, Ken; Lorey, Shelly L.; Lu, Bin; Wenzel, Sabine; Foshage, Audra M.; Alvarado, Joseph; Wang, Feng; Shaw, J. Grace; Zhao, Bin; Weissmiller, April M.; Thomas, Lance R.; Vakoc, Christopher R.; Hall, Matthew D. ; Hiebert, Scott W.; Liu, Qi; Stauffer, Shaun R.; Fesik, Stephen W.; Tansey, William P.

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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC); National Institutes of Health (NIH); Vanderbilt Ingram Cancer Center; Vanderbilt Digestive Disease Research Center; Vanderbilt Vision Research Center; National Cancer Institute (NCI); Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation; Alex’s Lemonade Stand Foundation
• Grant/Contract Number: AC02-06CH11357; 1S-10RR025677-01; CA68485; DK058404; EY008126; HHSN261200800001E; CA200709; CA211305
• OSTI ID: 1547648
• Alternate ID(s): OSTI ID: 1502226
• Journal Information: Cell Reports, Journal Name: Cell Reports Vol. 26 Journal Issue: 11; ISSN 2211-1247
• Publisher: Elsevier
• Country of Publication: Netherlands
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
chromatin
WDR5
small molecule inhibitor
ribosomal proteins
cancer
cancer therapy
gene expression
p53
nuclear stress
MLL