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5-phenyl-1,3,4-oxadiazol-2(3H)-ones are potent inhibitors of notum carboxylesterase activity identified by the optimization of a crystallographic fragment screening hit

DOI: 10.1021/acs.jmedchem.0c01391 DOI Help

Authors: William Mahy (University College London) , Nicky J. Willis (University College London) , Yuguang Zhao (Wellcome Centre for Human Genetics, University of Oxford) , Hannah L. Woodward (University College London) , Fredrik Svensson (University College London) , James Sipthorp (University College London) , Luca Vecchia (Wellcome Centre for Human Genetics, University of Oxford) , Reinis R. Ruza (Wellcome Centre for Human Genetics, University of Oxford) , James Hillier (Wellcome Centre for Human Genetics, University of Oxford) , Svend Kjær (The Francis Crick Institute) , Sarah Frew (University College London) , Amy Monaghan (University College London) , Magda Bictash (University College London) , Patricia C. Salinas (University College London) , Paul Whiting (University College London) , Jean-Paul Vincent (The Francis Crick Institute) , E. Yvonne Jones (Wellcome Trust Centre for Human Genetics, University of Oxford) , Paul V. Fish (The Francis Crick Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 16814

Abstract: Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood–brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.

Journal Keywords: Rodent models; Inhibitors,; Cell signaling; Inhibition; Central nervous system

Diamond Keywords: Enzymes

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

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

Added On: 02/11/2020 08:35

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening