SLU-PP-915 vs SR-9011

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).

SR-9011 is an agonist of the nuclear receptors REV-ERBα and REV-ERBβ. Binding enhances REV-ERB-mediated transcriptional repression (via NCoR corepressor recruitment), repressing core clock genes such as Bmal1 and downstream metabolic genes in liver, skeletal muscle, and adipose tissue (Solt et al., Nature 2012). All mechanistic data are from cells and rodents.

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