The Francis Crick Institute
acschemneuro.2c00325 (1).pdf (9.57 MB)

Structural analysis and development of Notum fragment screening hits.

Download (9.57 MB)
journal contribution
posted on 2022-07-07, 10:30 authored by Yuguang Zhao, William Mahy, Nicky J Willis, Hannah L Woodward, David Steadman, Elliott D Bayle, Benjamin N Atkinson, James Sipthorp, Luca Vecchia, Reinis R Ruza, Karl Harlos, Fiona Jeganathan, Stefan Constantinou, Artur Costa, Svend Kjær, Magda Bictash, Patricia C Salinas, Paul Whiting, Jean-Paul Vincent, Paul V Fish, E Yvonne Jones
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.


Crick (Grant ID: CC1068, Grant title: STP Structural Biology) Crick (Grant ID: CC2072, Grant title: Vincent CC2072)