PXD031338

PXD031338 is an original dataset announced via ProteomeXchange.

Title	Design of a potent, selective and brain penetrant inhibitor of Wnt-deactivating enzyme Notum by optimization of a crystallographic fragment hit
Description	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 disease such as colorectal cancer and Alzheimer’s disease supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we describe the discovery and profile of 8I (ARUK3001185) as a potent, selective and brain pentrant 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, identifed a pair of outstanding hits. Fragment development of these delivered 8I that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in proteomic and pharmacology screens showed 8I to be selective against serine hydrolases, kinases and drug targets.
HostingRepository	PRIDE
AnnounceDate	2022-06-09
AnnouncementXML	Submission_2022-06-09_02:06:36.591.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Steven Howell
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-30 14:21:15	ID requested
⏵ 1	2022-06-09 02:06:37	announced

Willis NJ, Mahy W, Sipthorp J, Zhao Y, Woodward HL, Atkinson BN, Bayle ED, Svensson F, Frew S, Jeganathan F, Monaghan A, Benvegn, ù S, Jolly S, Vecchia L, Ruza RR, Kj, æ, r S, Howell S, Snijders AP, Bictash M, Salinas PC, Vincent JP, Jones EY, Whiting P, Fish PV, Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit. J Med Chem, 65(10):7212-7230(2022) [pubmed]

submitter keyword: Notum, Inhibitor, Wnt signalling, Carboyxlesterase, LC-MSMS

Paul V. Fish
contact affiliation	Alzheimer’s Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London, WC1E 6BT, U.K.
contact email	p.fish@ucl.ac.uk
lab head
Steven Howell
contact affiliation	Francis Crick Institute
contact email	steven.howell@crick.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031338
     1. Label: PRIDE project
     2. Name: Design of a potent, selective and brain penetrant inhibitor of Wnt-deactivating enzyme Notum by optimization of a crystallographic fragment hit