8W0R

Human EBP complexed with compound 1

これはPDB形式変換不可エントリーです。

8W0R の概要

• エントリーDOI: 10.2210/pdb8w0r/pdb
• EMDBエントリー: 43712
• 分子名称: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase, 1-methyl-1'-[(oxan-4-yl)methyl]-5-(trifluoromethyl)spiro[indole-2,4'-piperidin]-3(1H)-one (2 entities in total)
• 機能のキーワード: emopamil-binding protein isomerization protein structure complex, structural protein, isomerase-inhibitor complex, isomerase/inhibitor
• 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: 55608.58

構造登録者

Sun, D.,Masureel, M. (登録日: 2024-02-14, 公開日: 2024-06-19)

主引用文献

Dorel, R.,Sun, D.,Carruthers, N.,Castanedo, G.M.,Ung, P.M.,Factor, D.C.,Li, T.,Baumann, H.,Janota, D.,Pang, J.,Salphati, L.,Meklemburg, R.,Korman, A.J.,Harper, H.E.,Stubblefield, S.,Payandeh, J.,McHugh, D.,Lang, B.T.,Tesar, P.J.,Dere, E.,Masureel, M.,Adams, D.J.,Volgraf, M.,Braun, M.G.
Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation.
J.Med.Chem., 67:4819-4832, 2024

PubMed Abstract: The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor demonstrated strong target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.

PubMed: 38470227
DOI: 10.1021/acs.jmedchem.3c02396

実験手法

ELECTRON MICROSCOPY (2.8 Å)