MOTS-c vs SLU-PP-915

Metabolic

Metabolic

Research Only

Research Only

MOTS-c acts primarily in skeletal muscle, where it activates AMPK — in part via inhibition of the folate cycle and de novo purine biosynthesis leading to AICAR accumulation — increasing glucose uptake and fatty acid oxidation. Interaction with the folliculin–FNIP complex has been proposed. An endocrine role is also reported, with serum MOTS-c levels declining with age, obesity, and type 2 diabetes.

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).

Not well characterized in humans; circulating half-life is short

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