SLU-PP-915 vs Sobetirome (GC-1)

Metabolic

Metabolic

Research Only

Research Only

The estrogen-related receptors (ERRα/β/γ) are orphan nuclear receptors that act as master transcriptional regulators of oxidative metabolism, driving mitochondrial biogenesis, oxidative phosphorylation, fatty-acid oxidation, and the TCA cycle — largely as partners of the PGC-1 coactivators. SLU-PP-915 binds and activates all three ERR isoforms with an EC50 of roughly 400 nM at each. In its medicinal-chemistry design, the phenol and aniline groups of earlier ERR agonists were replaced with a boronic-acid moiety on a disubstituted thiophene scaffold, which preserved receptor activity while improving microsomal metabolic stability and oral exposure. In cells and in rodents it upregulates canonical ERR target genes including PGC-1α, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 4 (PDK4), and DNA-damage-inducible transcript 4 (DDIT4).

Sobetirome acts as an agonist at thyroid hormone receptor beta (TRβ) with substantially reduced affinity for TRα, conferring tissue-selective thyromimetic activity. Structural features—an oxyacetic acid moiety and absence of the amino group found in T3—underlie its subtype selectivity in both binding and activation. In hypothyroid mice, this TRβ selectivity produced lipid-lowering effects comparable to T3 without the cardiac chronotropic (heart-rate) increase driven by TRα, supporting the design goal of metabolic benefit with reduced cardiac risk.

Not established in humans; engineered for improved metabolic stability and oral exposure relative to first-generation ERR agonists