Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity

By Benjamin N. Atkinson, N. Willis, Yuguang Zhao, C. Patel, S. Frew, K. Costelloe, L. Magno, Fredrik Svensson, E. Jones, Paul V. Fish. 2023

7 citations recorded by the source corpus.

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.

Subfields: Computational Theory and Mathematics, Molecular Biology, Organic Chemistry, Computational Chemistry & Drug Discovery