Inhibitor Report for: ARUK3001185

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.

ESTHER: Bayle_2021_J.Med.Chem__
PubMedSearch: Bayle 2021 J.Med.Chem
PubMedID: 33783220
Gene_locus related to this paper: human-NOTUM
Inhibitor(s) related to this paper: LP-922056, ARUK3001185, ABC99

Abstract

Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.

ESTHER: Zhao_2021_Future.Med.Chem__
PubMedSearch: Zhao 2021 Future.Med.Chem
PubMedID: 33882714
Gene_locus related to this paper: human-NOTUM
Inhibitor(s) related to this paper: 4F-329S, LP-914822, N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide, JVB, CHEMBL4539054, LP-922056, LP-935001, ARUK3001185, ABC99

Abstract

Notum has recently been identified as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group from Wnt proteins. There are emerging reports that Notum plays a role in human disease, with published data suggesting that targeting Notum could represent a new therapeutic approach for treating cancer, osteoporosis and neurodegenerative disorders. Complementary hit-finding strategies have been applied with successful approaches that include high-throughput screening, activity-based protein profiling, screening of fragment libraries and virtual screening campaigns. Structural studies are accelerating the discovery of new inhibitors of Notum. Three fit-for-purpose examples are LP-922056, ABC99 and ARUK3001185. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease.

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.

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: Bayle_2021_J.Med.Chem__
PubMedSearch: Bayle 2021 J.Med.Chem
PubMedID: 33783220
Gene_locus related to this paper: human-NOTUM
Inhibitor(s) related to this paper: LP-922056, ARUK3001185, ABC99

Abstract

Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.

ESTHER: Zhao_2021_Future.Med.Chem__
PubMedSearch: Zhao 2021 Future.Med.Chem
PubMedID: 33882714
Gene_locus related to this paper: human-NOTUM
Inhibitor(s) related to this paper: 4F-329S, LP-914822, N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide, JVB, CHEMBL4539054, LP-922056, LP-935001, ARUK3001185, ABC99

Abstract

Notum has recently been identified as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group from Wnt proteins. There are emerging reports that Notum plays a role in human disease, with published data suggesting that targeting Notum could represent a new therapeutic approach for treating cancer, osteoporosis and neurodegenerative disorders. Complementary hit-finding strategies have been applied with successful approaches that include high-throughput screening, activity-based protein profiling, screening of fragment libraries and virtual screening campaigns. Structural studies are accelerating the discovery of new inhibitors of Notum. Three fit-for-purpose examples are LP-922056, ABC99 and ARUK3001185. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease.

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.