6T2H
Furano[2,3-d]prymidine amides as Notum inhibitors
6T2H の概要
エントリーDOI | 10.2210/pdb6t2h/pdb |
分子名称 | Palmitoleoyl-protein carboxylesterase NOTUM, DIMETHYL SULFOXIDE, SULFATE ION, ... (7 entities in total) |
機能のキーワード | substrate, hydrolase |
由来する生物種 | Homo sapiens (Human) |
タンパク質・核酸の鎖数 | 1 |
化学式量合計 | 45702.73 |
構造登録者 | |
主引用文献 | Atkinson, B.N.,Steadman, D.,Mahy, W.,Zhao, Y.,Sipthorp, J.,Bayle, E.D.,Svensson, F.,Papageorgiou, G.,Jeganathan, F.,Frew, S.,Monaghan, A.,Bictash, M.,Jones, E.Y.,Fish, P.V. Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors. Bioorg.Med.Chem.Lett., 30:126751-126751, 2020 Cited by PubMed Abstract: The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum. PubMed: 31862412DOI: 10.1016/j.bmcl.2019.126751 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (1.41 Å) |
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