title: Molecular targets for 17α-ethynyl-5-androstene-3β,7β,17β-triol, an anti-inflammatory agent derived from the human metabolome.
abstract: HE3286, 17α-ethynyl-5-androstene-3β, 7β, 17β-triol, is a novel synthetic compound related to the endogenous sterol 5-androstene-3β, 7β, 17β-triol (β-AET), a metabolite of the abundant adrenal steroid dehydroepiandrosterone (DHEA). HE3286 has shown efficacy in clinical studies in impaired glucose tolerance and type 2 diabetes, and in vivo models of types 1 and 2 diabetes, autoimmunity, and inflammation. Proteomic analysis of solid-phase HE3286-bound bead affinity experiments, using extracts from RAW 264.7 mouse macrophage cells, identified 26 binding partners. Network analysis revealed associations of these HE3286 target proteins with nodes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for type 2 diabetes, insulin, adipokine, and adipocyte signaling. Binding partners included low density lipoprotein receptor-related protein (Lrp1), an endocytic receptor; mitogen activated protein kinases 1 and 3 (Mapk1, Mapk3), protein kinases involved in inflammation signaling pathways; ribosomal protein S6 kinase alpha-3 (Rsp6ka3), an intracellular regulatory protein; sirtuin-2 (Sirt2); and 17β-hydroxysteroid dehydrogenase 1 (Hsd17β4), a sterol metabolizing enzyme.
authors.affiliation: Department of Scientific Development, Harbor Biosciences, San Diego, California, United States of America.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Reading
authors.forename: James M
authors.initials: JM
authors.lastname: Frincke
authors.forename: Steven K
authors.initials: SK
authors.lastname: White
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000737:Androstenols / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015551:Autoimmunity; D002460:Cell Line; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D008956:Models, Chemical; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction
chemical_list: C524733:17-ethynyl-5-androstene-3, 7, 17-triol; C108492:5-androstene-3,7,17-triol; D000737:Androstenols; D000893:Anti-Inflammatory Agents; D003687:Dehydroepiandrosterone; D005947:Glucose