SLU-PP-332

This is the original report characterizing SLU-PP-332 as a synthetic pan-ERR agonist. In cotransfection assays in HEK293 cells, the compound activated ERRα, ERRβ, and ERRγ with EC50 values of 98, 230, and 430 nM respectively, with the highest potency at ERRα. In C2C12 mouse skeletal muscle cells, SLU-PP-332 induced PDK4 (pyruvate dehydrogenase kinase 4) expression, increased maximal mitochondrial respiration measured by Seahorse, and increased mitochondrial content as measured by MitoTracker staining. In mice dosed at 50 mg/kg b.i.d. intraperitoneally, the compound increased succinate dehydrogenase-positive type IIa oxidative skeletal muscle fibers in quadriceps, raised OXPHOS complex protein levels, and increased running endurance compared with vehicle. RNA-seq of quadriceps and gastrocnemius muscles showed significant overlap between SLU-PP-332-induced gene programs and the acute aerobic exercise transcriptional response in both mouse and human muscle datasets. Using ERRα-floxed conditional knockout mice, the authors demonstrated that the running endurance phenotype and induction of marker genes (Ddit4, Per1, Alas2) required ERRα.

Scientists wanted a small molecule they could use to switch on a family of cellular receptors called ERRs (estrogen-related receptors), which help regulate how muscle cells produce energy. They designed SLU-PP-332 and showed in lab dishes that it activates all three ERR family members, most strongly ERRα. In mouse muscle cells, the compound increased measurements of mitochondrial activity. When given to mice for about two weeks, it changed the muscle fiber composition toward more oxidative (endurance-type) fibers and the mice ran longer on a treadmill. By comparing the gene patterns in treated mouse muscle to gene patterns from actual aerobic exercise in mice and humans, the researchers found a significant overlap. They then used genetically modified mice missing ERRα in muscle to confirm the running effect depended specifically on ERRα. This established SLU-PP-332 as a useful chemical tool for studying ERR biology in animal models.

Follow-up work from the Burris laboratory examined SLU-PP-332 in mouse models of metabolic dysfunction. Diet-induced obese (DIO) mice and leptin-deficient ob/ob mice were dosed with SLU-PP-332 at 50 mg/kg b.i.d. intraperitoneally for 28 days. In DIO mice, the compound reduced fat mass, lowered serum cholesterol and triglycerides, and improved measures of insulin sensitivity, without altering food intake. Indirect calorimetry indicated increased whole-body energy expenditure and a shift toward greater fatty acid oxidation. Similar metabolic changes were observed in ob/ob mice. The authors discuss these findings in the context of ERR-driven transcriptional programs in skeletal muscle and other metabolic tissues, and frame SLU-PP-332 as a chemical tool for probing whether pharmacological activation of ERR signaling can modify metabolic phenotypes in rodent models.

After showing that SLU-PP-332 boosted endurance in normal mice, the same lab tested whether activating ERR signaling could change metabolic markers in mice with diet-induced obesity and in a leptin-deficient strain (ob/ob). Mice received the compound twice daily for four weeks. Researchers measured body composition, blood markers, and energy use in metabolic cages. Treated mice lost fat mass, had lower blood cholesterol and triglycerides, and showed better insulin response — and importantly, they were not eating less. The metabolic-cage data suggested the animals were burning more energy and using more fat as fuel. The study positions SLU-PP-332 as a research probe for asking whether targeting ERR receptors might be a useful direction for future metabolic research.