Structural analysis and development of Notum fragment screening hitsMore about Open Access at the Crick
Authors listYuguang 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 Kjaer 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.
Journal ACS Chemical Neuroscience
Issue number 13