1. Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.
- Author
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Atkinson BN, Willis NJ, Zhao Y, Patel C, Frew S, Costelloe K, Magno L, Svensson F, Jones EY, and Fish PV
- Subjects
- Biophysical Phenomena, Wnt Signaling Pathway, Carboxylic Ester Hydrolases
- 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., Competing Interests: Declaration of competing interest B.N.A., N.J.W, Y.Z., E.Y.J. and P.V.F. are co-inventors of patent application #WO 2020043866 issued to UCL Business Ltd, which describes inhibitors of Notum., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
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