Related Experiment Video

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Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling

Radu M Suciu1, Armand B Cognetta1, Zachary E Potter1

  • 1The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, United States.

ACS Medicinal Chemistry Letters
|June 26, 2018
PubMed

Insights

Researchers developed novel inhibitors targeting NOTUM, an enzyme that removes fatty acids from Wnt proteins. This discovery aids in understanding Wnt signaling and developing treatments for diseases like cancer and degenerative conditions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Wnt proteins are crucial morphogens in development and tissue repair.
  • Dysregulated Wnt signaling is linked to diseases, including cancer.
  • Wnt lipidation by porcupine (PORCN) and de-lipidation by NOTUM are key regulatory steps.

Purpose of the Study:

  • To discover and develop potent and selective inhibitors of the NOTUM enzyme.
  • To explore the therapeutic potential of NOTUM inhibition in Wnt-related diseases.

Main Methods:

  • Activity-based protein profiling (ABPP) was employed to identify NOTUM inhibitors.
  • A class of N-hydroxyhydantoin (NHH) carbamates was discovered.
  • An optimized inhibitor, ABC99, was developed and characterized.

Main Results:

  • NHH carbamates potently and selectively inhibit NOTUM.
  • The inhibitor ABC99 maintains Wnt signaling activity despite NOTUM presence.
  • ABC99 was adapted as an ABPP probe for NOTUM visualization.

Conclusions:

  • Novel NHH carbamate inhibitors of NOTUM were successfully developed using ABPP.
  • These inhibitors offer potential therapeutic strategies for Wnt-related pathologies.
  • The developed probe enables visualization of NOTUM in biological contexts.

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