Metabolic
A synthetic small-molecule pan-agonist of the estrogen-related receptors studied as a chemical probe for mitochondrial and oxidative-metabolism gene programs.
SLU-PP-332 is a synthetic small molecule that activates all three estrogen-related receptors (ERRα, ERRβ, ERRγ), a family of orphan nuclear receptors that regulate genes for mitochondrial biogenesis and oxidative metabolism. It was developed as a research tool to study how pharmacological ERR activation engages transcriptional programs governing mitochondrial energetics. It has been characterized in cell-based receptor assays and in rodent model systems of metabolic disease, cardiac stress, and aging, and is not a peptide.
Type
Synthetic small-molecule nuclear-receptor (ERR) pan-agonist; acylhydrazone (benzohydrazide) chemotype
Molecular formula
C18H14N2O2
Molecular weight
290.3 g/mol
CAS number
303760-60-3
SLU-PP-332 is a synthetic agonist of the estrogen-related receptors (ERRα, ERRβ, ERRγ), a subfamily of orphan nuclear receptors within the nuclear-receptor superfamily. Despite the name, ERRs do not bind estrogen; they are constitutively active transcription factors that, together with PGC-1α/β coactivators, regulate genes governing mitochondrial biogenesis, oxidative phosphorylation, fatty-acid oxidation, and the Krebs cycle. SLU-PP-332 was engineered from the ERRβ/γ-preferring agonist GSK4716 by medicinal-chemistry modification to add ERRα activity, producing a pan-agonist with preferential activity at ERRα. It binds within the ERR ligand-binding domain and stabilizes the receptor conformation that recruits the PGC-1 coactivator, increasing transcription of ERR target genes including Pdk4, Ddit4, and Slc25a25.
Research Focus
Studied in cell-based receptor assays and in preclinical metabolic, cardiac, and aging model systems as a chemical probe for ERR-coactivator transcriptional programs.
The acylhydrazone scaffold underlying SLU-PP-332 originated in a medicinal-chemistry program aimed at building ERRα activity into ligands that were previously ERRβ/γ-selective. Shahien et al. (2020) described the conversion of the ERRβ/γ-selective agonist GSK4716 into ERRα/β/γ pan-agonists, using molecular modeling and cell-based assays to map binding modes and measure agonist activity across isoforms. Billon et al. (2023) reported the identification and naming of SLU-PP-332 as the lead pan-ERR agonist of this series, characterizing its isoform activity profile in co-transfection reporter assays. Hampton et al. (2023) examined a structurally distinct 2,5-disubstituted thiophene series, identifying the related pan-ERR agonist SLU-PP-915. Most recently, Okda et al. (2026) reported a comprehensive structure–activity relationship study of the SLU-PP-332 scaffold, integrating chemical synthesis, cell-based functional assays, gene-expression profiling, and computational docking and molecular-dynamics modeling to map structural determinants of ERRα/ERRγ agonism, ligand efficiency, solubility, and metabolic stability.
SLU-PP-332 has been used as a reference chemical probe in cell-based systems. Billon et al. (2023) measured ERR-dependent transcription in skeletal-muscle cell lines, examining mitochondrial-biogenesis and oxidative-phosphorylation gene expression, oxygen consumption, and cellular respiration. The compound has been used to interrogate ERRα target genes including Pdk4, Ddit4, and Slc25a25 in C2C12 myocytes and myoblasts. Losby et al. (2024) characterized a mechanism by which ERR activation induces the autophagy–lysosome master regulator TFEB, examining TFEB as a direct ERR target gene and measuring autophagy-related gene expression in neonatal rat ventricular myocytes and C2C12 myoblasts.
A body of work positions SLU-PP-332 within skeletal-muscle and exercise-physiology research. Billon et al. (2023) examined an ERRα-dependent acute aerobic-exercise gene signature, type IIa oxidative muscle-fiber gene markers, and exercise-capacity endpoints in mouse model systems, using ERRα-null comparisons to assess isoform dependence. Wattez et al. (2023) generated skeletal-muscle-specific ERR knockout mice to examine ERR contributions to oxidative capacity in glycolytic versus oxidative muscle and characterized exercise-tolerance phenotypes. Fan et al. (2025) used genetic models to examine the cooperative and distinct roles of ERRα, ERRβ, and ERRγ in innate and adaptive muscle mitochondrial energetics. Billon et al. (2025) characterized the orally bioavailable analog SLU-PP-915, comparing administration routes and measuring Ddit4 and mitochondrial-gene induction relative to treadmill running; the parent SLU-PP-332 lacks oral bioavailability and was used as a reference comparator.
SLU-PP-332 has been administered in several rodent disease models to characterize ERR engagement and downstream gene programs. Billon et al. (2024) examined the compound in diet-induced obese and ob/ob mouse models of obesity and metabolic syndrome, assessing whole-body metabolic parameters including energy expenditure and fatty-acid oxidation gene programs. Xu et al. (2024) studied SLU-PP-332 and SLU-PP-915 in a pressure-overload mouse heart-failure model, using RNA-sequencing, metabolomics, and in vitro and in vivo genetic-dependency experiments to characterize cardiac fatty-acid-metabolism and mitochondrial gene programs and to identify the principal mediating ERR isoform.
Wang et al. (2023) administered SLU-PP-332 to aged mice in a study of the aging kidney, characterizing mitochondrial-function markers, albuminuria, podocyte markers, and inflammatory signaling alongside caloric-restriction comparators. Human work remains limited to ex vivo tissue: Bonanni et al. (2025) conducted a pilot study using primary myoblast cultures isolated from muscle biopsies of inactive elderly women, treating the cells with SLU-PP-332 to examine expression of metabolic markers including PGC-1α, ERRα, SIRT1, NOX4, and FNDC5. No registered human clinical trials of SLU-PP-332 have been identified.
Several analytical-chemistry studies have characterized the in vitro metabolic profile of SLU-PP-332 using human liver S9 fractions and microsomal systems. Avliyakulov et al. (2026) used LC–MS/HRMS to identify Phase I and Phase II metabolites of SLU-PP-332 in S9-fraction incubations. Möller, Krug, and Thevis (2026) characterized mass-spectrometric behavior and in vitro metabolic transformation products of SLU-PP-332 and SLU-PP-915 using S9 fractions and microsomes, with NMR confirmation of selected synthesized metabolites.
Lyophilized
Solid form is commonly stored desiccated and protected from light
vendor practice frequently specifies −20 °C for long-term stability.
Reconstituted
Typically first dissolved in DMSO
DMSO stock solutions are commonly stored at −20 °C. Aqueous working dilutions are prepared from DMSO stock.
Protect from light, moisture, and heat. Discard solutions showing discoloration or precipitation. Consult the specific certificate of analysis for any given lot.
Reviews
Sopariwala DH, Nguyen H, Narkar VA (2023). International Journal of Sports Medicine — Review of estrogen-related receptor signaling in skeletal-muscle homeostasis and fitness
Fan W, Atkins AR, Yu RT, Downes M, Evans RM (2013). Journal of Molecular Endocrinology — Review of nuclear-receptor targets for exercise-mimetic development in skeletal muscle
Clinical
Bonanni R, Falvino A, Matticari A, Rinaldi AM, D'Arcangelo G, Cifelli P, Iundusi R, Gasbarra E, Tancredi V, Cariati I, Tarantino U (2025). Frontiers in Physiology — Pilot study applying SLU-PP-332 to primary myoblasts from human muscle biopsies; metabolic-marker expression analysis
Primary research
Avliyakulov NK, Sobolevsky T, Ahrens E (2026). Drug Testing and Analysis — In vitro Phase I and Phase II metabolite identification of SLU-PP-332 by LC–MS/HRMS in human liver S9 fractions
Möller T, Krug O, Thevis M (2026). Rapid Communications in Mass Spectrometry — In vitro metabolism and mass-spectrometric characterization of metabolic transformation products of SLU-PP-332 and SLU-PP-915
Okda HE, Zhao P, Hayes M, Duvall C, Quillin E, Fang H, Mohammed BM, Hegazy L, Burris TP, Elgendy B (2026). International Journal of Biological Macromolecules — Structure–activity relationship study and computational analysis of the SLU-PP-332 acylhydrazone scaffold
Billon C, Appourchaux K, Côté I, Burris TP (2025). Journal of Pharmacology and Experimental Therapeutics — Pharmacological characterization of the orally bioavailable pan-ERR agonist SLU-PP-915; SLU-PP-332 used as reference comparator
Fan W, Oh TG, Wang HJ, et al. (2025). Proceedings of the National Academy of Sciences USA — Genetic analysis of the cooperative and distinct roles of ERRα, ERRβ, and ERRγ in muscle mitochondrial energetics
Losby M, Hayes M, Valfort A, Walker J, Xu W, Zhang L, Billon C, Burris TP (2024). Molecular Pharmacology — Mechanistic characterization of ERR-dependent regulation of autophagy via TFEB in cardiomyocytes and myoblasts
Billon C, Schoepke E, Avdagic A, Chatterjee A, Butler AA, Elgendy B, Walker JK, Burris TP (2024). Journal of Pharmacology and Experimental Therapeutics — Characterization of SLU-PP-332 in diet-induced obese and ob/ob mouse models of metabolic syndrome
Xu W, Billon C, Li H, et al. (2024). Circulation — Characterization of SLU-PP-332 and SLU-PP-915 in a pressure-overload mouse heart-failure model using RNA-sequencing and metabolomics
Wang XX, Myakala K, Libby AB, et al. (2023). The American Journal of Pathology — Characterization of pan-ERR agonist SLU-PP-332 in an aging mouse kidney model examining mitochondrial and inflammatory markers
Hampton CS, Sitaula S, Billon C, et al. (2023). European Journal of Medicinal Chemistry — Development and pharmacological evaluation of a thiophene-scaffold pan-ERR agonist series; identification of SLU-PP-915
Billon C, Sitaula S, Banerjee S, et al. (2023). ACS Chemical Biology — Identification and in vivo characterization of SLU-PP-332 as a pan-ERR agonist in ERRα-dependent muscle gene-program studies
Wattez JS, Eury E, Hazen BC, et al. (2023). Molecular Metabolism — Skeletal-muscle-specific ERR knockout study examining oxidative capacity and exercise-tolerance phenotypes
Shahien M, Elagawany M, Sitaula S, et al. (2020). Bioorganic Chemistry — Medicinal-chemistry conversion of GSK4716 to ERRα/β/γ pan-agonists; scaffold-origin characterization and binding-mode analysis
Also known as: SR9861
Research Use Only
These products are intended for research purposes only and are not for human consumption. Not FDA approved. Not intended to diagnose, treat, cure, or prevent any disease.
