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Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling

Bayle, ED; Svensson, F; Atkinson, BN; Steadman, D; Willis, NJ; Woodward, HL; Whiting, P; ... Fish, PV; + view all (2021) Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling. Journal of Medicinal Chemistry 10.1021/acs.jmedchem.0c01974. (In press).

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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.

Type: Article
Title: Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling
Location: United States
DOI: 10.1021/acs.jmedchem.0c01974
Publisher version: https://doi.org/10.1021/acs.jmedchem.0c01974
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10125984
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