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Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen

DOI: 10.1039/C9MD00096H DOI Help

Authors: Benjamin Nicholas Atkinson (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , David Steadman (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Yuguang Zhao (Wellcome Centre for Human Genetics, University of Oxford) , James Sipthorp (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute) , Luca Vecchia (Wellcome Centre for Human Genetics, University of Oxford) , Reinis Reinholds Ruza (Wellcome Centre for Human Genetics, University of Oxford) , Fiona Jeganathan (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Georgie Lines (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Sarah Frew (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Amy Monaghan (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Svend Kjaer (The Francis Crick Institute) , Magda Bictash (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford) , Paul V. Fish (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Medchemcomm

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 16814 , 14744

Open Access Open Access

Abstract: NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 μM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0.032 μM) and isoquinoline 45 (IC50 0.085 μM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray cocrystal structure determination which showed a flipped binding orientation compared to 3. However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.

Journal Keywords: NOTUM inhibitor; Wnt signaling; Alzheimer's disease; Crystallographic fragment screen; 2-Phenoxyacetamide; NADPH independent metabolism

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

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

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