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Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling

Elliott D Bayle1,2, Fredrik Svensson1,2, Benjamin N Atkinson1

  • 1Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.

Journal of Medicinal Chemistry
|March 30, 2021
PubMed

Insights

Inhibiting Notum carboxylesterase activity offers a novel therapeutic strategy for diseases linked to Wnt signaling pathway dysregulation. Small molecule inhibitors are being developed to target Notum, providing new tools for research and treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The Wnt signaling pathway is crucial for mammalian development and adult biology.
  • Aberrant Wnt signaling is implicated in various diseases.
  • Notum carboxylesterase negatively regulates Wnt signaling by removing a palmitoleate group.

Purpose of the Study:

  • To summarize therapeutic opportunities in modulating Wnt signaling.
  • To highlight the potential of inhibiting Notum carboxylesterase activity.
  • To present small molecule inhibitors of Notum as research tools.

Main Methods:

  • Review of current literature on Wnt signaling and Notum.
  • Discussion of screening technologies for Notum inhibitors.
  • Optimization of identified hits into small molecule inhibitors.

Main Results:

  • Notum's role as a negative regulator of Wnt signaling is established.
  • Screening and structural studies have accelerated the discovery of Notum inhibitors.
  • Several potent small molecule inhibitors, including LP-922056, ABC99, and ARUK3001185, have been developed.

Conclusions:

  • Inhibition of Notum activity presents a promising therapeutic avenue for diseases associated with its aberrant function.
  • Developed small molecule inhibitors serve as valuable chemical tools for further investigation of Notum's role in Wnt signaling.
  • Targeting Notum offers a new strategy for treating diseases driven by Wnt pathway dysregulation.

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