Atkinson, Benjamin N;
Willis, Nicky J;
Zhao, Yuguang;
Patel, Chandni;
Frew, Sarah;
Costelloe, Kathryn;
Magno, Lorenza;
... Fish, Paul V; + view all
(2023)
Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.
European Journal of Medicinal Chemistry
, 251
, Article 115132. 10.1016/j.ejmech.2023.115132.
Preview |
Text
1-s2.0-S0223523423000478-main (1).pdf Download (3MB) | Preview |
Abstract
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.
Archive Staff Only
 |
View Item |
