Structural analysis and development of notum fragment screening hits

DOI: 10.1021/acschemneuro.2c00325

Authors: Yuguang Zhao (ellcome Centre for Human Genetics, University of Oxford) , William Mahy (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Nicky J. Willis (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Hannah L. Woodward (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , David Steadman (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Elliott D. Bayle (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute) , Benjamin N. Atkinson (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , James Sipthorp (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute) , Luca Vecchia (Wellcome Centre for Human Genetics, University of Oxford) , Reinis R. Ruza (The Wellcome Centre for Human Genetics, University of Oxford) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , Fiona Jeganathan (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Stefan Constantinou (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Artur Costa (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Svend Kjær (The Francis Crick Institute) , Magda Bictash (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Patricia C. Salinas (University College London) , Paul Whiting (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Jean-Paul Vincent (The Francis Crick Institute) , Paul V. Fish (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Neuroscience

State: Published (Approved)
Published: June 2022
Diamond Proposal Number(s): 16814

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.

Journal Keywords: Notum inhibitors; fragment screening; Diamond-SGC Poised Library (DSPL); hit-to-lead development; Wnt signaling

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 27/06/2022 08:41

Documents:
acschemneuro.2c00325.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening