2. Academic Validation
  3. 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

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

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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