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ABC99

目录号 : GC42669

An inhibitor of NOTUM

ABC99 Chemical Structure

Cas No.:2331255-53-7

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500ug
¥1,139.00
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1mg
¥2,149.00
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5mg
¥7,816.00
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产品描述

ABC99 is an N-hydroxyhydantoin (NHH) carbamate that inhibits the Wnt-deacylating enzyme NOTUM (IC50 = 13 nM).[1] It preserves Wnt3A signaling in the presence of NOTUM (EC50 = 89 nM in a cell-based reporter assay).

Reference:
[1]. Suciu, R.M., Cognetta, A.B., III., Potter, Z.E., et al. Selective irreversible inhibitors of the Wnt-deacylating enzyme NOTUM developed by activity-based protein profiling. ACS Med. Chem. Lett. 9(6), 563-568 (2018).

Chemical Properties

Cas No. 2331255-53-7 SDF
化学名 7-(4-chlorobenzyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate
Canonical SMILES ClC1=CC=C(CN2CC(C(N(OC(N3C(C=CC=C4)=C4OCC3)=O)C5=O)=O)N5CC2)C=C1
分子式 C22H21ClN4O5 分子量 456.9
溶解度 1mg/mL in Chloroform, 1mg/mL in acetonitrile, 1mg/mL in methyl acetate 储存条件 Store at -20°C
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储备液的保存方式和期限:-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。
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1 mM 2.1887 mL 10.9433 mL 21.8866 mL
5 mM 0.4377 mL 2.1887 mL 4.3773 mL
10 mM 0.2189 mL 1.0943 mL 2.1887 mL
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Research Update

Small-molecule inhibitors of carboxylesterase Notum

Future Med Chem 2021 Jun;13(11):1001-1015.PMID:33882714DOI:10.4155/fmc-2021-0036.

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.

Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling

J Med Chem 2021 Apr 22;64(8):4289-4311.PMID:33783220DOI:10.1021/acs.jmedchem.0c01974.

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.

Roads to the Fountain of Youth? Rejuvenating Intestinal Stem Cells

Rejuvenation Res 2019 Aug;22(4):342-347.PMID:31364468DOI:10.1089/rej.2019.2251.

The intestinal stem cells (ISCs) of old mice and humans exhibit a reduced capacity for regeneration and repair. Compromised intestinal function may play a key role in systemic aging-related changes: not only in the affected gut, but also in the nervous and cardiovascular systems. For example, progression of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's has been linked to increased inflammation from gut microbiota in old mammals, which, in turn, may be linked bidirectionally with reduced ISC function. Intestinal organoid formation has been used to dissect the mechanisms of decline of ISC function. Alterations of the Wnt pathway, including downregulation of Wnt ligands in ISCs and upregulation of Wnt ligand inhibitor Notum in Paneth cells, and dysregulation of mTORC1 contribute to the observed age-related decline. Short-term fasting, caloric restriction, and peroxisome proliferator-activated receptor delta agonists have been reported to increase ISC function in adult mice. Moreover, the mTOR inhibitor rapamycin, NAD+ precursor nicotinamide riboside, and ABC99, a small molecule Notum inhibitor, have all been reported to rejuvenate ISC function in old mice and thus may have promise in humans. However, there is some controversy over the key mechanisms involved in loss of function of ISCs, which likely results, in part, from differences in how the in vitro organoid assays are performed. Moreover, how the microbiome modulates the function of ISCs and vice versa remains to be elucidated.

Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling

ACS Med Chem Lett 2018 May 26;9(6):563-568.PMID:29937983DOI:10.1021/acsmedchemlett.8b00191.

Wnt proteins are secreted morphogens that play critical roles in embryonic development and tissue remodeling in adult organisms. Aberrant Wnt signaling contributes to diseases such as cancer. Wnts are modified by an unusual O-fatty acylation event (O-linked palmitoleoylation of a conserved serine) that is required for binding to Frizzled receptors. O-Palmitoleoylation of Wnts is introduced by the porcupine (PORCN) acyltransferase and removed by the serine hydrolase NOTUM. PORCN inhibitors are under development for oncology, while NOTUM inhibitors have potential for treating degenerative diseases. Here, we describe the use of activity-based protein profiling (ABPP) to discover and advance a class of N-hydroxyhydantoin (NHH) carbamates that potently and selectively inhibit NOTUM. An optimized NHH carbamate inhibitor, ABC99, preserves Wnt-mediated cell signaling in the presence of NOTUM and was also converted into an ABPP probe for visualizing NOTUM in native biological systems.

Notum suppresses the osteogenic differentiation of periodontal ligament stem cells through the Wnt/Beta catenin signaling pathway

Arch Oral Biol 2021 Oct;130:105211.PMID:34352447DOI:10.1016/j.archoralbio.2021.105211.

Objectives: The aims of this study were to explore: (ⅰ) the effect of Notum on periodontitis in vivo; (ⅱ) the effect of Notum on the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in vitro; and (ⅲ) the potential mechanism of Notum in inhibiting the osteogenic differentiation of hPDLSCs. Design: C57BL/6J mice were randomly assigned into two groups: control group (n = 4) and periodontitis group (n = 4). Immunohistochemical staining was used to evaluate the expression of Notum. In in vitro experiments, Western blot, qRT- PCR and ELISA were used to examine the expression of Notum in a lipopolysaccharide-induced inflammation model. Alkaline phosphatase staining was used to evaluate alkaline phosphatase activity. Western blot and qRT - PCR were used to measure the expression of osteogenic-related markers after adding human recombinant Notum and Notum inhibitor ABC99. In addition, LiCl, an agonist of the Wnt/Beta-catenin signaling pathway, was added to explore using Western blot whether Notum was involved in regulating the osteogenic differentiation of human periodontal ligament stem cells through the Wnt/Beta-catenin signaling pathway. Results: Notum was highly expressed in periodontal tissues of mice and lipopolysaccharide-induced inflammation cell model. The protein and messenger ribonucleic acid levels of hPDLSCs osteogenic markers were reduced after adding human recombinant Notum. However, the inhibitory effect of Notum on the osteogenic differentiation of hPDLSCs could be significantly reversed by adding LiCl. Conclusion: These results demonstrated that Notum inhibited the osteogenic differentiation of hPDLSCs probably via the Wnt/Beta-catenin the downstream signaling pathway.