SLU-PP-915

SLU-PP-915 is a synthetic small molecule that activates all three estrogen-related receptors, ERR alpha, ERR beta and ERR gamma. It came from the same Saint Louis University and Center for Clinical Pharmacology program as SLU-PP-332, but from a different chemical family: a 2,5-disubstituted thiophene amide carrying a phenylboronic acid group rather than an acylhydrazone.

The swap was deliberate, since the authors saw the acyl hydrazide scaffold of the earlier series as a potential liability in vivo, and the boronic acid analogs held half-lives over 60 minutes in mouse and human liver microsomes (Hampton et al., 2023). It is not a peptide: no amino acids, no peptide bonds.

The literature here is thin, and worth stating plainly: a PubMed search for SLU-PP-915 returns six records, four original experiments and two reviews, and two more use it without naming it in the abstract. Every primary paper except the doping-control analysis carries authors from the laboratories that made it, and most of what is known about pan-ERR agonism comes from the older SLU-PP-332, cited below where it carries the point. Six areas follow, each with its model.

Where it came from

A medicinal chemistry paper screened 2,5-disubstituted thiophenes designed from the ERR gamma crystal structure bound to GSK4716, confirmed binding by proton nuclear magnetic resonance, and carried compound 10s, SLU-PP-915, forward. It raised the ERR target genes PGC-1 alpha, LDHA and PDK4 in C2C12 mouse myoblasts at 5 micromolar, and in male C57BL/6J mice a single 20 mg/kg amount raised PDK4, PGC-1 alpha and Ddit4 in quadriceps within one hour. Mice on the same amount for six days ran further and longer on a treadmill than vehicle controls (Hampton et al., 2023). Models: reporter assays, C2C12 cells, mice.

Receptor activity and selectivity

Reports differ a little on potency, since laboratories ran different assay formats. The identifying paper put its half maximal effective concentration at 378 nanomolar for ERR gamma, with roughly equivalent activity at ERR alpha and beta (Hampton et al., 2023), a flatter profile than SLU-PP-332, which favors ERR alpha (Billon et al., 2023).

A later cotransfection assay reported about 450 nanomolar at ERR alpha and gamma and about 1.8 micromolar at ERR beta, with no activity at other receptors tested (Xu et al., 2024). A 2026 review calls it one of the most interesting preclinical ERR agonists, while flagging that its boronic acid group can bond covalently to proteins other than the target (Radwan et al., 2026). Models: transfected cells.

Heart failure models and ERR gamma dependence

The largest study used transverse aortic constriction in mice, a pressure overload model of heart failure, with 25 mg/kg twice daily by intraperitoneal injection for six weeks. Ejection fraction stayed above vehicle controls from week two, stroke volume and cardiac output held up, fibrosis was lower, survival was higher, and cardiac hypertrophy was unchanged. Isolated heart mitochondria kept their respiration, and the authors reported no overt toxicity. In mice without ERR gamma in cardiomyocytes none of the cardiac effects appeared, tying the mechanism to that receptor (Xu et al., 2024). Models: wild-type and knockout mice.

Autophagy genes in heart and muscle cells

Working from the heart failure data, the same group asked how ERR activation reaches the autophagy pathway. In neonatal rat ventricular myocytes at 2.5 micromolar for 72 hours, and in C2C12 myoblasts at 5 micromolar, SLU-PP-915 raised transcription factor EB messenger RNA and protein by 40 to 50 percent, about what nutrient starvation did, along with p62, PDK4 and PGC-1 alpha. Reporter assays showed the promoter responds to each of the three ERRs, and SLU-PP-332 gave a similar pattern (Losby et al., 2024). Models: rat cardiomyocytes, mouse myoblasts.

Oral activity, running capacity and brown fat

The clearest reason this compound exists is bioavailability: a 2026 paper reports that SLU-PP-915 is orally bioavailable, which SLU-PP-332 is not, and that it raised running distance and duration in mice by either route once systemic exposure was matched. Both compounds raised Ddit4 in muscle, and with exercise training the compound pushed Ddit4 and mitochondrial gene expression higher still (Billon et al., 2026). Separately, a Danish group found that mice receiving 20 mg/kg twice daily for five days raised Gpr3, a thermogenic receptor gene, in brown fat (Sveidahl Johansen et al., 2026). Models: male C57BL/6 mice.

Metabolism and doping-control analysis

A doping-control laboratory in Cologne characterised both SLU compounds by liquid chromatography with high-resolution mass spectrometry, then incubated them with human liver S9 fractions and microsomes. SLU-PP-915 gave seven Phase I transformation products and no Phase II conjugates, with the boronic acid oxidised to a hydroxyl in several; three were confirmed by synthesis and nuclear magnetic resonance.

SLU-PP-332 gave nine metabolites, three of them Phase II conjugates (Möller et al., 2026). Models: human liver fractions in vitro.