Structure Report for: 6ZUV

Zhao, Y.,Jones, E.Y.

Title: Design of a potent, selective and brain penetrant inhibitor of Wnt-deactivating enzyme Notum by optimization of a crystallographic fragment hit
Willis NJ, Mahy W, Sipthorp J, Zhao Y, Woodward HL, Atkinson BN, Bayle ED, Svensson F, Frew S and Fish PV <14 more author(s)> Willis NJ, Mahy W, Sipthorp J, Zhao Y, Woodward HL, Atkinson BN, Bayle ED, Svensson F, Frew S, Jeganathan F, Monaghan A, Benvegnu S, Jolly S, Vecchia L, Ruza RR, Kjaer S, Howell SA, Snidjers AP, Bictash M, Salinas PC, Vincent JP, Jones EY, Whiting P, Fish PV (- 14)
Ref: Journal of Medicinal Chemistry, :, 2022 : PubMed
Abstract


ESTHER: Willis_2022_J.Med.Chem__
PubMedSearch: Willis 2022 J.Med.Chem
PubMedID: 35536179
Gene_locus related to this paper: human-NOTUM
Inhibitor(s) related to this paper: ARUK3001043, Fragment-077, ARUK3001185

Abstract

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'ss disease supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we describe the discovery and profile of 8l (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 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.



        

Title: Structural Analysis and Development of Notum Fragment Screening Hits
Zhao Y, Mahy W, Willis NJ, Woodward HL, Steadman D, Bayle ED, Atkinson BN, Sipthorp J, Vecchia L and Jones EY <11 more author(s)> Zhao Y, Mahy W, Willis NJ, Woodward HL, Steadman D, Bayle ED, Atkinson BN, Sipthorp J, Vecchia L, Ruza RR, Harlos K, Jeganathan F, Constantinou S, Costa A, Kjaer S, Bictash M, Salinas PC, Whiting P, Vincent JP, Fish PV, Jones EY (- 11)
Ref: ACS Chem Neurosci, 13:2060, 2022 : PubMed
Abstract


ESTHER: Zhao_2022_ACS.Chem.Neurosci_13_2060
PubMedSearch: Zhao 2022 ACS.Chem.Neurosci 13 2060
PubMedID: 35731924
Gene_locus related to this paper: human-NOTUM
Inhibitor(s) related to this paper: CHEMBL57478, ARUK3001043, Fragment-823, Fragment-828, Fragment-810, Fragment-872, Fragment-863, Fragment-791, Fragment-772, Fragment-784, Fragment-792, Fragment-705, Fragment-722, Fragment-714, Fragment-658, Fragment-690, Fragment-923, Fragment-924, Fragment-900, Fragment-916, Fragment-934, Fragment-955, Fragment-927, ARUK3000223, Fragment-886, Fragment-067, Fragment-074, Fragment-077, Fragment-065, Fragment-154, Fragment-159, Felbinac, Fragment-174, Fragment-173, Fragment-110, Sulfapyridine, Fragment-147, Fragment-297, Fragment-290, Fragment-201, Fragment-210, Fragment-283, Fragment-282, Fragment-277, Fragment-276, Fragment-197, Fragment-193, Fragment-199, Fragment-588, Fragment-609, Fragment-634, Fragment-646, Fragment-830, 2-N-pyridin-2-ylbenzene-1,2-diamine, (4-fluoroanilino)thiourea, Fragment-063-notum-screen, Fragment-064-notum-screen, Fragment-049-notum-screen, SCHEMBL21776992, 4F-329S, N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide, JVB, CHEMBL4539054, ARUK3001185

Abstract

The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 microM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC(50) 0.0067 microM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.



        

Title: 5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit
Mahy W, Willis NJ, Zhao Y, Woodward HL, Svensson F, Sipthorp J, Vecchia L, Ruza RR, Hillier J and Fish PV <8 more author(s)> Mahy W, Willis NJ, Zhao Y, Woodward HL, Svensson F, Sipthorp J, Vecchia L, Ruza RR, Hillier J, Kjr S, Frew S, Monaghan A, Bictash M, Salinas PC, Whiting P, Vincent JP, Jones EY, Fish PV (- 8)
Ref: Journal of Medicinal Chemistry, 63:12942, 2020 : PubMed
Abstract


ESTHER: Mahy_2020_J.Med.Chem_63_12942
PubMedSearch: Mahy 2020 J.Med.Chem 63 12942
PubMedID: 33124429
Inhibitor(s) related to this paper: SCHEMBL21776992, 4F-329S, ARUK3001185

Abstract

Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.