Zhao, Yuguang;
Mahy, William;
Willis, Nicky J;
Woodward, Hannah L;
Steadman, David;
Bayle, Elliott D;
Atkinson, Benjamin N;
... Jones, E Yvonne; + view all
(2022)
Structural Analysis and Development of Notum Fragment Screening Hits.
ACS Chemical Neuroscience
, 13
(13)
pp. 2060-2077.
10.1021/acschemneuro.2c00325.
Preview |
Text
Fish_acschemneuro.2c00325.pdf - Published Version Download (9MB) | Preview |
Abstract
The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.
| Type: | Article |
|---|---|
| Title: | Structural Analysis and Development of Notum Fragment Screening Hits |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acschemneuro.2c00325 |
| Publisher version: | https://doi.org/10.1021/acschemneuro.2c00325 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors. Published by American Chemical Society. This is an open access article under the CC BY 4.0 license Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0/) |
| Keywords: | Diamond-SGC Poised Library (DSPL), Notum inhibitors, Wnt signaling, fragment screening, hit-to-lead development |
| UCL classification: | 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 > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10151338 |
Archive Staff Only
 |
View Item |
