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6T2H

Furano[2,3-d]prymidine amides as Notum inhibitors

6T2H の概要
エントリーDOI10.2210/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
Zhao, Y.,Jones, E.Y. (登録日: 2019-10-08, 公開日: 2020-01-01, 最終更新日: 2024-11-06)
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: 31862412
DOI: 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)
構造検証レポート
Validation report summary of 6t2h
検証レポート(詳細版)ダウンロードをダウンロード

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件を2024-11-06に公開中

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