SLU-PP-332 is a synthetic small molecule that switches on the estrogen-related receptors, a trio of nuclear receptors (ERRα, ERRβ and ERRγ) that help set how much mitochondrial and fat-burning machinery a cell builds. It came out of a medicinal chemistry program led by Thomas Burris’s group, then at Saint Louis University, which is where the “SLU” prefix comes from.
Interest in the compound grew quickly after the group described it as a pharmacological tool that reproduces parts of the gene program seen after aerobic exercise in mouse muscle. This overview covers the receptor biology behind it, the published mouse and cell work, and the substantial gaps that remain in a literature that is still young.
At a glance
- Class: Synthetic small molecule; pan-ERR agonist with the highest activity at ERRα
- Origin: Burris laboratory, Saint Louis University; first full description by Billon and colleagues in 2023
- Structure: Aryl acylhydrazone; C18H14N2O2; MW 290.3 g/mol; CAS 303760-60-3
- Main research areas: ERR pharmacology, skeletal muscle gene programs, metabolic mouse models, cardiac metabolism
- Regulatory status: Not approved by the FDA; no published human studies; research reagent only
Structure and origin
The estrogen-related receptors were found in the late 1980s by sequence similarity to the estrogen receptor, but they do not bind estradiol. They are “orphan” receptors with no confirmed natural ligand, and they are active on their own, recruiting coactivators such as PGC-1α and PGC-1β without needing a hormone. For years the available chemical tools were mostly inverse agonists that switch the receptors off, plus a few acylhydrazone agonists that favored ERRβ and ERRγ.
SLU-PP-332 grew out of that acylhydrazone chemistry. Structurally it joins a 4-hydroxybenzoyl hydrazide to a naphthaldehyde through a hydrazone (C=N–NH) linkage, giving a small, flat, fairly lipophilic molecule. Billon and colleagues reported that it activated all three ERR isoforms in cell-based transactivation assays, with its strongest activity at ERRα, the isoform that had lacked a usable synthetic agonist (Billon et al., 2023).
Mechanism: what the research shows
ERRα and ERRγ are highly expressed in tissues that burn a lot of energy: heart, skeletal muscle, kidney and brown fat. Together with PGC-1 coactivators, they bind ERR response elements in the promoters of genes for mitochondrial biogenesis, the tricarboxylic acid cycle, fatty-acid oxidation and oxidative phosphorylation. Knockout mice lacking ERRα have reduced capacity to adapt to energetic stress, which helped establish the receptor as a regulator of oxidative metabolism.
In the first SLU-PP-332 paper, the compound increased expression of ERR target genes and mitochondrial respiration in C2C12 mouse muscle cells. In mice, it induced an oxidative gene program in skeletal muscle. Experiments in cells with reduced ERRα indicated that much of the response depended on that isoform (Billon et al., 2023). The pharmacology published so far rests largely on reporter assays, gene-expression panels, respirometry and mouse tissue analysis.
Key areas of study
Skeletal muscle and the exercise gene program
The headline finding of the 2023 study was that SLU-PP-332 triggered in mouse muscle a set of transcriptional changes overlapping with those seen after a bout of aerobic exercise. The authors also reported more oxidative (type IIa) fibers and longer treadmill running in treated mice than in controls (Billon et al., 2023). Because these are mouse data from one laboratory, they describe a model readout rather than a general effect.
Metabolic syndrome models
A follow-up paper tested the compound in diet-induced obese mice and in genetically obese ob/ob mice. In these models the group reported higher whole-body energy expenditure and fatty-acid oxidation, reduced fat mass accumulation and better insulin sensitivity than in vehicle-treated animals, along with changes in ERR target genes in muscle and other tissues (Billon et al., 2024). The study framed ERR activation as a way to examine the link between mitochondrial gene programs and whole-body metabolism.
Cardiac metabolism and heart failure models
The failing heart shifts away from fatty-acid oxidation, and ERRα and ERRγ are key drivers of cardiac mitochondrial genes. In collaboration with cardiovascular groups, the same team reported that pan-ERR agonists from this chemical series increased fatty-acid metabolism and mitochondrial function in cardiomyocytes and were associated with preserved cardiac function in a mouse pressure-overload model of heart failure (Xu et al., 2024). This extended ERR agonist research from skeletal muscle into the heart.
What the evidence does not show
The published SLU-PP-332 literature is small, recent and almost entirely from one research network, and independent replication is limited. All of the in vivo work is in mice, so species differences in drug handling and ERR biology have not been addressed. Full pharmacokinetic, toxicology and off-target profiles have not been published in detail, and the acylhydrazone linkage can be hydrolytically and metabolically labile, which complicates interpretation of in vivo data. There are no published human studies of any kind. Calling the compound an “exercise mimetic” describes overlapping gene-expression changes in mouse muscle; it does not mean the full physiology of exercise has been reproduced.
Regulatory status
SLU-PP-332 is not approved by the FDA, has not been tested in published human studies, and is not approved for human use. It is sold by Rogue Compounds as a research reagent only.
Handling and storage in the lab
SLU-PP-332 capsules should be kept sealed at room temperature (20–25°C), away from heat, moisture and light. Leave the pouch closed between uses so the dry fill is not exposed to humidity.
Sourcing and documentation
Rogue Compounds has SLU-PP-332 made in small batches. Every batch is tested by an independent U.S. lab and the batch COA is on the product page and in the COA Library.
View SLU-PP-332 on Rogue Compounds
References
- Billon C, et al. Synthetic ERRα/β/γ agonist induces an ERRα-dependent acute aerobic exercise response and enhances exercise capacity. ACS Chem Biol. 2023;18(4):756-771. PMID 36988910
- Billon C, et al. A synthetic ERR agonist alleviates metabolic syndrome. J Pharmacol Exp Ther. 2024;388(2):232-240. PMID 37739806
- Xu W, et al. Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function. Circulation. 2024;149(3):227-250. PMID 37961903
Research use only. Rogue Compounds products are sold strictly for laboratory research. They are not for human or veterinary use, and nothing in this article is medical advice. The studies cited here describe published research, not this product or any use of it.