+検索条件
-Structure paper
タイトル | Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation. |
---|---|
ジャーナル・号・ページ | J Med Chem, Vol. 67, Issue 6, Page 4819-4832, Year 2024 |
掲載日 | 2024年3月28日 |
著者 | Ruth Dorel / Dawei Sun / Nicholas Carruthers / Georgette M Castanedo / Peter M-U Ung / Daniel C Factor / Tianbo Li / Hannah Baumann / Danielle Janota / Jodie Pang / Laurent Salphati / Robert Meklemburg / Allison J Korman / Halie E Harper / Samantha Stubblefield / Jian Payandeh / Daniel McHugh / Bradley T Lang / Paul J Tesar / Edward Dere / Matthieu Masureel / Drew J Adams / Matthew Volgraf / Marie-Gabrielle Braun / |
PubMed 要旨 | 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 ...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. |
リンク | J Med Chem / PubMed:38470227 |
手法 | EM (単粒子) |
解像度 | 2.8 Å |
構造データ | EMDB-43712, PDB-8w0r: EMDB-43713, PDB-8w0s: |
化合物 | PDB-1aeu: PDB-1aev: |
由来 |
|
キーワード | ISOMERASE/INHIBITOR / Emopamil-Binding Protein Isomerization Protein structure complex / STRUCTURAL PROTEIN (タンパク質) / ISOMERASE-INHIBITOR complex |