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Impact of WIN site inhibitor on the WDR5 interactome

Alissa D Guarnaccia1, Kristie L Rose2, Jing Wang3

  • 1Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Cell Reports
|January 20, 2021
PubMed

Insights

WIN site inhibitors alter the WDR5 interactome, impacting cancer-related signaling pathways. This study identifies PDPK1 as a key WDR5 binding protein influencing cell cycle gene transcription.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Proteomics

Background:

  • The chromatin-associated protein WDR5 is a validated therapeutic target in oncology.
  • Current drug discovery focuses on inhibiting the WDR5 WIN site, an arginine-binding cavity.
  • The precise effects of WIN site inhibition on WDR5's protein interaction network (interactome) are not well understood.

Purpose of the Study:

  • To investigate the impact of WIN site inhibition on the WDR5 interactome using quantitative proteomics.
  • To identify specific WDR5-interacting proteins affected by WIN site inhibitors.
  • To explore the functional consequences of altered WDR5 interactions, particularly in relation to cancer signaling.

Main Methods:

  • Quantitative proteomics was employed to analyze changes in the WDR5 interactome.
  • The study focused on identifying proteins whose interactions with WDR5 are modulated by WIN site inhibition.
  • Proof-of-concept experiments were conducted to validate key findings, including protein-protein interactions and functional assays.

Main Results:

  • WIN site inhibition significantly altered the interactions of WDR5 with dozens of proteins.
  • Affected proteins include components of the phosphatidylinositol 3-kinase (PI3K) signaling pathway.
  • The master kinase PDPK1 was identified as a high-affinity WIN site binding protein that interacts with WDR5.

Conclusions:

  • WIN site inhibition broadly remodels the WDR5 interactome, extending beyond direct binding site effects.
  • WDR5, through its interaction with PDPK1, plays a role in modulating the transcription of G2 phase cell cycle genes.
  • This research provides a valuable dataset and mechanistic insights into WDR5 function and the action of WIN site inhibitors in cancer.
Keywords:
PDPK1WDR5cancer therapychromatin

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