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Carboxylesterase notum is a druggable target to modulate Wnt signaling

DOI: 10.1021/acs.jmedchem.0c01974 DOI Help

Authors: Elliott D. Bayle (University College London; The Francis Crick Institute) , Fredrik Svensson (University College London; The Francis Crick Institute) , Benjamin N. Atkinson (University College London) , David Steadman (University College London) , Nicky J. Willis (University College London) , Hannah L. Woodward (University College London) , Paul Whiting (University College London) , Jean-Paul Vincent (The Francis Crick Institute) , Paul V. Fish (University College London; The Francis Crick Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 117

State: Published (Approved)
Published: March 2021

Abstract: Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: NONE-No attached Diamond beamline

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening