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Impact of WIN site inhibitor on the WDR5 interactome.
Authors Guarnaccia AD, Rose KL, Wang J, Zhao B, Popay TM, Wang CE, Guerrazzi K, Hill S,
Woodley CM, Hansen TJ, Lorey SL, Shaw JG, Payne WG, Weissmiller AM, Olejniczak
ET, Fesik SW, Liu Q, Tansey WP
Submitted By Submitted Externally on 2/22/2021
Status Published
Journal Cell reports
Year 2021
Date Published 1/1/2021
Volume : Pages 34 : 108636
PubMed Reference 33472061
Abstract The chromatin-associated protein WDR5 is a promising pharmacological target in
cancer, with most drug discovery efforts directed against an arginine-binding
cavity in WDR5 called the WIN site. Despite a clear expectation that WIN site
inhibitors will alter the repertoire of WDR5 interaction partners, their impact
on the WDR5 interactome remains unknown. Here, we use quantitative proteomics to
delineate how the WDR5 interactome is changed by WIN site inhibition. We show
that the WIN site inhibitor alters the interaction of WDR5 with dozens of
proteins, including those linked to phosphatidylinositol 3-kinase (PI3K)
signaling. As proof of concept, we demonstrate that the master kinase PDPK1 is a
bona fide high-affinity WIN site binding protein that engages WDR5 to modulate
transcription of genes expressed in the G2 phase of the cell cycle. This dataset
expands our understanding of WDR5 and serves as a resource for deciphering the
action of WIN site inhibitors.


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