SLU-PP-915: Molecular Mechanism of Action and Preclinical Studies
SLU-PP-915 (chemical identifier: 2,5-disubstituted thiophene amide with boronic acid; CAS not specified in primary sources) is a synthetic, orally bioavailable pan-agonist of the estrogen-related receptors (ERRα, ERRβ, and ERRγ). It was developed through structure-based optimization of a new acyl hydrazide-derived chemical series at Saint Louis University, distinct from the earlier pan-ERR agonist SLU-PP-332. The key innovation is the incorporation of a boronic acid moiety, which replaces phenolic or aniline groups found in prior scaffolds. This modification enhances metabolic stability and maintains potent agonist activity across all three ERR isoforms (EC₅₀ values ≈ 414 nM for ERRα, 435 nM for ERRβ, and 378 nM for ERRγ).
No human clinical trials have been conducted or reported as of April 2026. All available data are preclinical (in vitro cell assays, ex vivo tissues, and animal models). SLU-PP-915 remains an experimental research tool.
Molecular Mechanism of Action (MOA)
At the molecular level, SLU-PP-915 functions as a direct ligand that binds the ligand-binding domain (LBD) of ERRs. Binding was validated using biophysical methods, including ¹H NMR protein-ligand titration experiments with the ERRγ LBD. The boronic acid group acts as a hydrogen-bond donor, stabilizing the receptor-ligand complex in a manner that mimics natural phenolic interactions in earlier agonists.
Ligand binding induces a conformational shift in the ERR LBD, promoting recruitment of coactivators such as PGC-1α. This activates ERR-dependent transcription at ERR response elements (ERREs) in promoter regions of target genes.
Primary upregulated pathways include:
• Mitochondrial biogenesis and oxidative phosphorylation (OXPHOS): Induction of PPARGC1A (PGC-1α), electron transport chain components, and TCA cycle enzymes (e.g., Aco2, Sdhb).
• Fatty acid oxidation (FAO) and metabolic reprogramming: Upregulation of PDK4, ACSL1, CPT1B, and ACADM, shifting cellular energy utilization toward fatty acids and mitochondrial efficiency.
• Exercise-mimetic and stress-response genes: Induction of DDIT4 and LDHA.
• Autophagy and lysosomal biogenesis: Activation of TFEB, leading to increased expression of LAMP1, LAMP2, CTSD, MCOLN1, and p62/SQSTM1, supporting autophagic flux and cellular maintenance.
ERRγ appears to be a dominant mediator of these effects in cardiomyocytes and skeletal muscle, although the compound demonstrates balanced activity across all ERR isoforms. Genetic knockdown studies confirm that a large proportion of transcriptional changes induced by SLU-PP-915 are ERR-dependent, with ERRγ contributing significantly to metabolic pathway regulation.
The overall effect observed in experimental systems is a shift toward enhanced mitochondrial function, fatty acid oxidation, and cellular energy efficiency.
Preclinical Studies and Observed Effects
1. Exercise Capacity and Skeletal Muscle
In controlled experimental models, SLU-PP-915 administration (oral and parenteral routes) was associated with measurable increases in endurance-related parameters, including running distance and duration in treadmill-based assays.
Gene expression analysis demonstrated induction of metabolic and mitochondrial pathways consistent with endurance adaptation. Chronic exposure in combination with training protocols further amplified oxidative and mitochondrial gene programs.
Pharmacokinetic evaluations indicate improved oral bioavailability compared to earlier compounds in this class, supporting its use in research models examining systemic metabolic regulation.
2. Cardiovascular Research Models
In pressure-overload experimental models, SLU-PP-915 administration was associated with improvements in cardiac functional parameters, including left ventricular performance and metabolic gene expression profiles.
Observed effects included:
• modulation of cardiac energy metabolism
• improved mitochondrial structure and function
• reduced markers associated with fibrotic remodeling
These outcomes were strongly linked to ERRγ-mediated signaling pathways in cardiac tissue.
3. Autophagy and Cellular Maintenance
In cellular models, SLU-PP-915 exposure was associated with increased TFEB expression and activation of lysosomal and autophagy-related gene networks.
This translated to:
• enhanced autophagic flux
• increased lysosomal activity
• improved clearance of damaged cellular components
These findings support its relevance in studies examining cellular maintenance, stress response, and metabolic adaptation.
Translational Research Context (Allometric Models)
In preclinical research, exposure frameworks are sometimes evaluated using allometric scaling approaches to compare biological responses across species.
For SLU-PP-915, experimental exposure ranges have been explored in controlled animal models to investigate metabolic, mitochondrial, and cardiovascular outcomes. These values are used exclusively for comparative and mechanistic research purposes.
All findings remain within preclinical contexts and are not intended to represent human application parameters.
Comparative Research Context
| Parameter |
SLU-PP-332 |
SLU-PP-915 |
| Chemical Scaffold |
Acyl hydrazide-based |
2,5-disubstituted thiophene amide with boronic acid |
| Key Structural Feature |
Phenolic/aniline groups |
Boronic acid moiety |
| Oral Bioavailability |
Limited |
Improved |
| Metabolic Stability |
Lower |
Higher |
| ERRα EC₅₀ |
98 nM |
414 nM |
| ERRβ EC₅₀ |
~230 nM |
435 nM |
| ERRγ EC₅₀ |
~430 nM |
378 nM |
| Potency Profile |
ERRα-preferring |
Balanced pan-ERR agonist |
| Exercise Model Effects |
Increased endurance parameters |
Comparable effects with improved exposure profile |
| Cardiovascular Models |
Improved functional markers |
Comparable metabolic and functional outcomes |
Summary
SLU-PP-915 is an orally active pan-ERR agonist studied in experimental models for its effects on metabolic regulation, mitochondrial function, fatty acid oxidation, and autophagy.
Preclinical studies demonstrate its role in modulating transcriptional programs associated with energy metabolism and cellular adaptation, with ERRγ playing a central role in mediating these effects.
All available data remain within controlled laboratory and preclinical research contexts.
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