5-Phenyl-1,3,4-oxadiazol-2(3 H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit

  • J Med Chem. 2020 Nov 12;63(21):12942-12956. doi: 10.1021/acs.jmedchem.0c01391.
William Mahy  1 ,  Nicky J Willis  1 ,  Yuguang Zhao  2 ,  Hannah L Woodward  1 ,  Fredrik Svensson  1  3 ,  James Sipthorp  1  3 ,  Luca Vecchia  2 ,  Reinis R Ruza  2 ,  James Hillier  2 ,  Svend Kjær  3 ,  Sarah Frew  1 ,  Amy Monaghan  1 ,  Magda Bictash  1 ,  Patricia C Salinas  4 ,  Paul Whiting  1 ,  Jean-Paul Vincent  3 ,  E Yvonne Jones  2 ,  Paul V Fish  1  3
Affiliations
  • 1. Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • 2. Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, U.K.
  • 3. The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
  • 4. Department of Cell and Developmental Biology, Laboratory for Molecular and Cellular Biology, University College London, London WC1E 6BT, U.K.
PMID: 33124429 DOI: 10.1021/acs.jmedchem.0c01391
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.

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