SLU-PP-915

Identity a synthetic small molecule that activates the estrogen-related receptors (ERRα, ERRβ, ERRγ) — orphan nuclear receptors — to mimic aspects of aerobic exercise ("exercise mimetic"). It is the orally-bioavailable successor to SLU-PP-332 (#60), from the same laboratory, and is a chemically distinct scaffold built specifically to overcome #60's limitations. ## Mechanism (as proposed) the estrogen-related receptors (ERRα/β/γ) are orphan nuclear receptors — structurally related to estrogen receptors but not activated by estrogens — that act as master transcriptional regulators of mitochondrial biogenesis, oxidative phosphorylation, fatty-acid oxidation, and the Krebs cycle, and are essential for skeletal-muscle adaptation to aerobic exercise. SLU-PP-915 is a pan-agonist (hitting all three, with ERRα central to the effect) that induces Ddit4 — a driver of the acute aerobic-exercise transcriptional program — and thereby increases maximal exercise capacity and oxidative (type-IIa) muscle fibers. The advance over #60 is purely pharmacokinetic-chemical: a new scaffold (boronic-acid thiophene) engineered from ERRγ crystal-structure data to be orally absorbed while preserving the same receptor pharmacology — so the mechanism is shared with #60, but the deliverability (in mice) is new.