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Structural insights into notum covalent inhibition

DOI: 10.1021/acs.jmedchem.1c00701 DOI Help

Authors: Yuguang Zhao (Wellcome Centre for Human Genetics, University of Oxford) , Fredrik Svensson (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , David Steadman (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) , Magda Bictash (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Tiago Moreira (Centre for Medicines Discovery, University of Oxford) , Rod Chalk (Centre for Medicines Discovery, University of Oxford) , Weixian Lu (Wellcome Centre for Human Genetics, University of Oxford) , Paul V. Fish (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 19946

Open Access Open Access

Abstract: The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer’s disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.

Journal Keywords: Chemical structure; Assays; Inhibitors; Organic compounds; Alkyls

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


Instruments: I03-Macromolecular Crystallography

Added On: 26/07/2021 08:20

Documents:
acs.jmedchem.1c00701.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)