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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
PubMed

Insights

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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