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Screening of a custom-designed acid fragment library identifies 1-phenylpyrroles and 1-phenylpyrrolidines as inhibitors of Notum carboxylesterase activity

DOI: 10.1021/acs.jmedchem.0c00660 DOI Help

Authors: William Mahy (University College London) , Mikesh Patel (University College London) , David Steadman (University College London) , Hannah L. Woodward (University College London) , Benjamin N. Atkinson (University College London) , Fredrik Svensson (University College London; The Francis Crick Institute) , Nicky J. Willis (University College London) , Alister Flint (University College London) , Dimitra Papatheodorou (University College London) , Yuguang Zhao (Wellcome Centre for Human Genetics, University of Oxford) , Luca Vecchia (Wellcome Centre for Human Genetics, University of Oxford) , Reinis R. Ruza (Wellcome Centre for Human Genetics, University of Oxford) , James Hillier (Wellcome Centre for Human Genetics, University of Oxford) , Sarah Frew (University College London) , Amy Monaghan (University College London) , Artur Costa (University College London) , Magda Bictash (University College London) , Magnus Walter (Eli Lilly) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford) , Paul V. Fish (University College London; The Francis Crick Institute)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 19946 , 14744

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, 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.

Journal Keywords: Notum inhibitor; Wnt signaling, fragment library; structure-based drug design; 1-phenylpyrroles; 1-phenylpyrrolidines

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 03/08/2020 09:11

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)