Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling

• Published in: Journal of medicinal chemistry Vol. 64; no. 8; pp. 4289 - 4311
• Main Authors: Bayle, Elliott D, Svensson, Fredrik, Atkinson, Benjamin N, Steadman, David, Willis, Nicky J, Woodward, Hannah L, Whiting, Paul, Vincent, Jean-Paul, Fish, Paul V
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.04.2021
• Subjects: Binding Sites; Catalytic Domain; Cell Nucleus - metabolism; Cytoplasm - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Esterases - antagonists & inhibitors; Esterases - metabolism; Humans; Molecular Dynamics Simulation; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology; Wnt Signaling Pathway - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01974

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.