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

Erin R Aho1, Jing Wang2, Rocco D Gogliotti3

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

Cell Reports
|March 14, 2019
PubMed

Insights

WIN site inhibitors block the chromatin protein WDR5, impacting cancer-related ribosome genes. This leads to reduced protein production and may offer new cancer treatment strategies.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Pharmacology

Background:

  • The chromatin-associated protein WDR5 is a key target for cancer drug development.
  • Current drug discovery focuses on inhibiting the WDR5 WIN site, but the precise WDR5 target genes and inhibitor effects are not fully understood.

Purpose of the Study:

  • To investigate the role of the WDR5 WIN site in chromatin association and gene regulation.
  • To elucidate the primary effects of WIN site inhibitors in cancer contexts.

Main Methods:

  • Discovery and application of potent small molecule WIN site inhibitors.
  • Analysis of WDR5 chromatin binding and gene expression changes.
  • Assessment of downstream cellular effects including translation, nucleolar stress, and p53 induction.

Main Results:

  • The WDR5 WIN site was found to link WDR5 to a specific set of chromatin loci, including ribosome protein genes.
  • WIN site inhibitors rapidly displaced WDR5 from chromatin and decreased target gene expression.
  • Inhibitor treatment resulted in translational inhibition, nucleolar stress, and p53 activation.

Conclusions:

  • WDR5 engages chromatin via its WIN site, regulating a specific cohort of genes.
  • WIN site blockade effectively inhibits WDR5 function, leading to cancer-relevant cellular responses.
  • Targeting the WDR5 WIN site shows promise for treating various cancer types.
Keywords:
MLLWDR5cancercancer therapychromatingene expressionnucleoar stressp53ribosomal proteinssmall molecule inhibitor

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