Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity
- Eur J Med Chem. 2023 May 5;251:115132. doi: 10.1016/j.ejmech.2023.115132.
- 1. Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
- 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, UK.
- 3. Alzheimer's Research UK UCL Drug Discovery Institute, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK. Electronic address: [email protected].
N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.