Inhibitor Report for: SCHEMBL21776992

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.

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.