8S77

Soluble epoxide hydrolase in complex with PROTAC JSF234

これはPDB形式変換不可エントリーです。

8S77 の概要

• エントリーDOI: 10.2210/pdb8s77/pdb
• 関連するPDBエントリー: 8S75 8S76
• 分子名称: Bifunctional epoxide hydrolase 2, 1,2-ETHANEDIOL, ~{N}-[[4-(cyclopropylsulfonylamino)-2-(trifluoromethyl)phenyl]methyl]-1-ethylsulfonyl-indole-5-carboxamide, ... (5 entities in total)
• 機能のキーワード: complex, structural genomics, structural genomics consortium, sgc, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85501.87

構造登録者

Kumar, A.,Schoenfeld, J.,Hiesinger, K.,Lillich, F.,Proschak, E.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2024-02-29, 公開日: 2025-03-12, 最終更新日: 2025-09-24)

主引用文献

Schonfeld, J.,Brunst, S.,Ciomirtan, L.,Willmer, L.,Chromik, M.A.,Kumar, A.,Froemel, T.,Liebisch, N.,Hackspacher, A.,Ehrler, J.H.M.,Wintermeier, L.,Hesse, C.,Fiedler, J.,Heering, J.,Freitag, H.,Zardo, P.,Fieguth, H.G.,Bruggerhoff, A.,Jakob, J.,Haupl, B.,Weizel, L.,Kaiser, A.,Schubert-Zsilavecz, M.,Oellerich, T.,Fleming, I.,Schebb, N.H.,Furst, R.,Kannt, A.,Knapp, S.,Proschak, E.,Hiesinger, K.
Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase.
J.Med.Chem., 68:13728-13749, 2025

PubMed Abstract: The bifunctional soluble epoxide hydrolase (sEH) represents a promising target for inflammation-related diseases. Although potent inhibitors targeting each domain are available, sEH-PROTACs offer the unique ability to simultaneously block both enzymatic functions, mimicking the sEH knockout phenotype, which has been associated with reducing inflammation, including neuroinflammation, and delaying the progression of Alzheimer's disease. Herein, we report the structure-based development of a potent sEH-PROTAC as a useful pharmacological tool. In order to facilitate a rapid testing of the PROTACs, a cell-based sEH degradation assay was developed utilizing HiBiT technology. We designed and synthesized 24 PROTACs. Furthermore, cocrystallization of sEH with two selected PROTACs allowed us to explore the binding mode and rationalize the most optimal linker length. After comprehensive biological and physicochemical characterization of this series, the most optimal PROTAC was identified in primary human and murine cells, highlighting the potential of using in disease-relevant cell and tissue models.

PubMed: 40532036
DOI: 10.1021/acs.jmedchem.5c00552

実験手法

X-RAY DIFFRACTION (1.36 Å)