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WIN site inhibition disrupts a subset of WDR5 function
Andrew J Siladi1, Jing Wang2,3, Andrea C Florian1
1Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, 465 21st Avenue South, Nashville, TN, 37232, USA.
Scientific Reports
|February 4, 2022
Summary
WIN site inhibitors only partially disable WDR5, and histone H3 lysine 4 methylation changes do not drive cancer cell responses. This suggests distinct therapeutic applications for WDR5 inhibitors and degraders.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- WDR5 is crucial for assembling histone-modifying complexes and has roles beyond this in chromatin regulation.
- WDR5 is a key pharmacological target in cancer, with drug discovery focusing on inhibiting its WIN site.
- WIN site inhibitors are assumed to broadly disable WDR5 functions and alter histone H3 lysine 4 methylation (H3K4me) to drive cancer cell transcriptional responses.
Purpose of the Study:
- To investigate the assumptions underlying the therapeutic application of WDR5 WIN site inhibitors.
- To compare the effects of WIN site inhibition versus WDR5 degradation on H3K4me and cellular transcription.
- To elucidate the precise mechanisms of action for WDR5-targeting drugs.
Main Methods:
- Comparative analysis of WDR5 WIN site inhibition and WDR5 degradation.
- Assessment of H3K4me levels following WDR5 manipulation.
- Transcriptional profiling of cancer cells treated with WDR5 inhibitors or degraders.
Main Results:
- WIN site inhibition affects only a subset of WDR5 activities.
- H3K4me alterations resulting from WDR5 depletion do not account for observed transcriptional changes.
- WDR5 degradation leads to different outcomes compared to WIN site inhibition.
Conclusions:
- WIN site inhibitors function as selective loss-of-function agents, not broad inhibitors of WDR5.
- H3K4me is not the primary mechanism driving cancer cell transcriptional responses to WDR5 inhibitors.
- WIN site inhibitors and WDR5 degraders possess distinct clinical applications and therapeutic potential.
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