Mahy, W; Patel, M; Steadman, D; Woodward, HL; Atkinson, BN; Svensson, F; Willis, NJ; ... Fish, PV; + view all Mahy, W; Patel, M; Steadman, D; Woodward, HL; Atkinson, BN; Svensson, F; Willis, NJ; Flint, A; Papatheodorou, D; Zhao, Y; Vecchia, L; Ruza, RR; Hillier, J; Frew, S; Monaghan, A; Costa, A; Bictash, M; Walter, MW; Jones, EY; Fish, PV; - view fewer (2020) Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity. Journal of Medicinal Chemistry , 63 (17) pp. 9464-9483. 10.1021/acs.jmedchem.0c00660.

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Abstract

The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.

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