Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit | Zendy

Nicky J. Willis | Zendy; William Mahy | Zendy; James Sipthorp | Zendy; Yuguang Zhao | Zendy; Hannah L. Woodward | Zendy; Benjamin N. Atkinson | Zendy; Elliott D. Bayle | Zendy; Fredrik Svensson | Zendy; Sarah Frew | Zendy; Fiona Jeganathan | Zendy; Amy E. Monaghan | Zendy; Stefano Benvegnù | Zendy; Sarah Jolly | Zendy; Luca Vecchia | Zendy; Reinis R. Ruza | Zendy; Susanne K. Kjær | Zendy; Steven Howell | Zendy; Ambrosius P. Snijders | Zendy; Magda Bictash | Zendy; Patricia C. Salinas | Zendy; JeanPaul Vincent | Zendy; E. Yvonne Jones | Zendy; Paul J. Whiting | Zendy; Paul V. Fish | Zendy

Open Access

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

Author(s) -

Nicky J. Willis,

William Mahy,

James Sipthorp,

Yuguang Zhao,

Hannah L. Woodward,

Benjamin N. Atkinson,

Elliott D. Bayle,

Fredrik Svensson,

Sarah Frew,

Fiona Jeganathan,

Amy E. Monaghan,

Stefano Benvegnù,

Sarah Jolly,

Luca Vecchia,

Reinis R. Ruza,

Susanne K. Kjær,

Steven Howell,

Ambrosius P. Snijders,

Magda Bictash,

Patricia C. Salinas,

JeanPaul Vincent,

E. Yvonne Jones,

Paul J. Whiting,

Paul V. Fish

Publication year - 2022

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.2c00162

Subject(s) - wnt signaling pathway , chemistry , enzyme , neurodegeneration , biochemistry , drug discovery , computational biology , pharmacology , signal transduction , biology , disease , medicine , pathology

Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.

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