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TitleDiscovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation.
Journal, issue, pagesJ Med Chem, Vol. 67, Issue 6, Page 4819-4832, Year 2024
Publish dateMar 28, 2024
AuthorsRuth 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 AbstractThe 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.
External linksJ Med Chem / PubMed:38470227
MethodsEM (single particle)
Resolution2.8 Å
Structure data

43712

8w0r

EMDB-43712, PDB-8w0r:
Human EBP complexed with compound 1
Method: EM (single particle) / Resolution: 2.8 Å

43713

8w0s

EMDB-43713, PDB-8w0s:
Human EBP complexed with compound 3a
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

PDB-1aeu:
SPECIFICITY OF LIGAND BINDING IN A POLAR CAVITY OF CYTOCHROME C PEROXIDASE (2-METHYLIMIDAZOLE)

PDB-1aev:
INTRODUCTION OF NOVEL SUBSTRATE OXIDATION INTO CYTOCHROME C PEROXIDASE BY CAVITY COMPLEMENTATION: OXIDATION OF 2-AMINOTHIAZOLE AND COVALENT MODIFICATION OF THE ENZYME (2-AMINOTHIAZOLE)

Source
  • homo sapiens (human)
KeywordsISOMERASE/INHIBITOR / Emopamil-Binding Protein Isomerization Protein structure complex / STRUCTURAL PROTEIN / ISOMERASE-INHIBITOR complex

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