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.

A synthetic anti‐inflammatory sterol improves insulin sensitivity in insulin‐resistant obese impaired glucose tolerance subjects

“…The selectivity of HE3286 responses may be better understood based on recent investigations of HE3286‐binding partners, which were discovered using affinity chromatography and SILAC (stable‐isotope labeling in culture) proteomic analysis tools . We have evidence for direct interactions between HE3286 and both extracellular receptor kinase (ERK) 1 and 2, in addition to other binding partners.…”

An Anti-Inflammatory Sterol Decreases Obesity-Related Inflammation-Induced Insulin Resistance and Metabolic Dysregulation

“…We designed this study to test the hypothesis, based on preclinical data and on molecular studies of HE3286 binding partners, that HE3286 would decrease the hyperactivation of NFkB with consequent restoration of insulin signaling [5, 6], dependent on its interaction with extracellular signal regulated kinase (ERK) 1 and 2 [7] in addition to other binding partners. ERK1 is an important mediator of inflammation-induced insulin resistance [23–25], insulin receptor substrate (IRS)-1 serine (inhibitory) phosphorylation, and the inhibitory effect of TNF α on insulin signaling [26].…”

“…In addition, HE3286 reduced liver cholesterol and triglyceride content, leading to a feedback elevation of low-density lipoprotein (LDL) receptor and decreased total serum cholesterol [5]. Recently, we have reported that HE3286 binds to Erk1/2, Lrp1, and Sirt2 [7] and proposed that the HE3286-mediated decrease in hyperactivation of Erk1/2 may be causal for its metabolic [8] and anti-inflammatory activities. …”

17α-Ethynyl-androst-5-ene-3β,7β,17Nicoletti1, Philippens2, Fagone3 et al. 2012Parkinson's DiseaseSelf Cite8270View full textAdd to dashboardCite

“…HE3286 ERK binding [19] and regulation of ERK activation [20] may be responsible for the anti-inflammatory and neuroprotective effects observed in the current study. MPTP initiates a neuroinflammatory sequence involving (among other inflammatory mediators) high mobility group box 1 (HMGB1) that prolongs ERK activation [11].…”

“…HE3286 has no known intrinsic neuropharmacological activity or toxicity [13]. HE3286 binds ERK1/2, low-density lipoprotein receptor-related protein 1 (Lrp1) and sirtuin 2 (Sirt2) [19], and HE3286 decreases ERK1/2 activation in lipopolysaccharide-(LPS)-stimulated rodent macrophages [20]. HE3286 is a Phase II clinical development compound with a good safety profile in humans to date (manuscript submitted).…”