Atkinson_2023_Eur.J.Med.Chem_251_115132

Reference

Title : Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity - Atkinson_2023_Eur.J.Med.Chem_251_115132
Author(s) : Atkinson BN , Willis NJ , Zhao Y , Patel C , Frew S , Costelloe K , Magno L , Svensson F , Jones EY , Fish PV
Ref : Eur Journal of Medicinal Chemistry , 251 :115132 , 2023
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.
ESTHER : Atkinson_2023_Eur.J.Med.Chem_251_115132
PubMedSearch : Atkinson_2023_Eur.J.Med.Chem_251_115132
PubMedID: 36934521
Gene_locus related to this paper: human-NOTUM

Related information

Gene_locus related to this paper: human-NOTUM

Citations formats

Atkinson BN, Willis NJ, Zhao Y, Patel C, Frew S, Costelloe K, Magno L, Svensson F, Jones EY, Fish PV (2023)
Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity
Eur Journal of Medicinal Chemistry 251 :115132

Atkinson BN, Willis NJ, Zhao Y, Patel C, Frew S, Costelloe K, Magno L, Svensson F, Jones EY, Fish PV (2023)
Eur Journal of Medicinal Chemistry 251 :115132