Pan-ERR Agonists Complete Guide 2026: SLU-PP-915, SLU-PP-332, DY131, GSK4716 & XCT-790 — Mechanism, CAS & Pre-clinical Research
The estrogen-related receptor (ERR) toolbox in one place — five synthetic nuclear-receptor ligands spanning pan-agonists (SLU-PP-915, SLU-PP-332), ERRβ/γ-selective agonists (DY131, GSK4716), and the lone inverse agonist (XCT-790). We cover ERRα/β/γ biology, CAS numbers, EC50 values, the "exercise-mimetic" mechanism, published preclinical readouts, SAR, and how to pick the right probe for your assay.
At a Glance
ERRα/β/γ are orphan nuclear receptors (no endogenous ligand) that drive mitochondrial biogenesis, oxidative phosphorylation and the aerobic-exercise transcriptional program. A single small-molecule toolbox now covers the whole family — but only two are true pan-agonists, two are isoform-selective, and one (XCT-790) is an inverse agonist that also uncouples mitochondria. All are preclinical-only research chemicals.
Table of Contents
- ERR / Pan-ERR Agonist Family Snapshot
- CAS Numbers & Chemical Identity
- ERR Biology: Orphan Nuclear Receptors & Energy Metabolism
- Mechanism of Action — Ligand-Binding Domain & Coactivator Recruitment
- SLU-PP-915 Deep Dive
- SLU-PP-332 Deep Dive
- DY131 (GSK 9089) Deep Dive
- GSK4716 Deep Dive
- XCT-790 Deep Dive — Inverse Agonist & Uncoupler
- Isoform Selectivity & Head-to-Head Comparison
- Preclinical Findings Across Models
- Research Applications & Decision Guide
- SAR: From Acyl-Hydrazides to Boronic Acids
- Product Quality, Solubility & Sourcing Notes
- Frequently Asked Questions
- Conclusion
1. ERR / Pan-ERR Agonist Family Snapshot
The estrogen-related receptor (ERR) ligand family is small but chemically diverse. In a single comparator table, the five most cited research compounds look like this:
| Compound | CAS | ERR Activity | Scaffold | Key Feature | Status |
|---|---|---|---|---|---|
| SLU-PP-915 | 2285432-92-8 | Pan-ERR agonist (α/β/γ) | 2,5-Disubstituted thiophene, boronic acid | Next-gen of SLU-PP-332; improved oral PK; NMR-validated binding | Preclinical (tool) |
| SLU-PP-332 | 303760-60-3 | Pan-ERR agonist (α/β/γ) | Acyl hydrazide, naphthalene | First-generation exercise mimetic; robust in vivo dataset | Preclinical (tool) |
| DY131 (GSK 9089) | 95167-41-2 | ERRβ/γ-selective agonist; inactive ERRα | Acyl hydrazide, diethylamino | Also a Smoothened (Smo) antagonist; cancer/bone tool | Preclinical (tool) |
| GSK4716 | 101574-65-6 | ERRβ/γ agonist, minimal ERRα | Acyl hydrazide, isopropyl | GSK-originated; ERRγ inverse-agonist label in some lit. | Preclinical (tool) |
| XCT-790 | 725247-18-7 | ERRα-selective INVERSE agonist | Trifluoromethyl thiadiazole acrylamide | Also a nanomolar mitochondrial uncoupler (FCCP-like) | Preclinical (tool) |
2. CAS Numbers & Chemical Identity
| Compound | CAS | Formula | MW | Synonyms |
|---|---|---|---|---|
| SLU-PP-915 | 2285432-92-8 | C17H13BFNO3S | 341.16 | Compound 10s; B-[3-[5-[[(2-fluorophenyl)amino]carbonyl]-2-thienyl]phenyl]boronic acid |
| SLU-PP-332 | 303760-60-3 | C18H14N2O2 | 290.32 | (E)-4-Hydroxy-N'-(naphthalen-2-ylmethylene)benzohydrazide |
| DY131 | 95167-41-2 | C18H21N3O2 | 311.38 | GSK 9089; GW4716; GSK4716; N'-[(E)-(4-diethylaminophenyl)methylene]-4-hydroxybenzohydrazide |
| GSK4716 | 101574-65-6 | C17H18N2O2 | 282.34 | 4-Hydroxybenzoic acid 2-[[4-(1-methylethyl)phenyl]methylene]hydrazide |
| XCT-790 | 725247-18-7 | C23H13F9N4O3S | 596.42 | (2E)-3-(4-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-methoxyphenyl)-2-cyano-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]acrylamide |
- SLU-PP-915 is uniquely identifiable by the boronic acid moiety (B-containing formula) — a deliberate replacement for the phenol/aniline H-bond donor of earlier scaffolds.
- DY131 and GSK4716 share the acyl-hydrazide class but differ by the N-aryl substituent (diethylamino vs. isopropyl) — they are not interchangeable.
- XCT-790's nine fluorines and thiadiazole make it chemically distinct; PubChem CID 6918788.
3. ERR Biology: Orphan Nuclear Receptors & Energy Metabolism
ERRα (gene ESRRA), ERRβ (ESRRB) and ERRγ (ESRRG) are orphan nuclear receptors — despite the name, estrogens neither bind them nor activate them. They are constitutively active, relying on coactivators such as PGC-1α and PGC-1β rather than a ligand for basal tone.
Tissue distribution
- ERRα — most abundant; high in heart, skeletal muscle, kidney, intestine and brown adipose tissue. Strongly exercise-responsive.
- ERRβ — more restricted, lower expression; prominent in CNS and some developing tissues.
- ERRγ — heart, kidney and high-energy-demand tissues; dominant mediator of metabolic gene programs in cardiomyocytes and oxidative muscle.
What ERRs control
Activated ERRs drive transcription at ERR response elements (ERREs) of genes governing:
- Mitochondrial biogenesis — PPARGC1A (PGC-1α), NRF, TFAM
- Oxidative phosphorylation — electron-transport-chain subunits (SDHB, ACO2…)
- Fatty-acid oxidation — CPT1B, ACSL1, ACADM, PDK4
- Exercise adaptation — LDHA, DDIT4 (acute aerobic-exercise markers)
- Autophagy / lysosomal biogenesis — TFEB, LAMP1/2, p62/SQSTM1
4. Mechanism of Action — Ligand-Binding Domain & Coactivator Recruitment
All five compounds act on the ERR ligand-binding domain (LBD), but as agonism vs. inverse agonism:
Agonist path (SLU-PP-915, SLU-PP-332, DY131, GSK4716)
- Small molecule binds the ERR LBD (direct, biophysically confirmed for SLU-PP-915 vs. ERRγ by 1H NMR titration).
- The boronic-acid / phenolic H-bond donor stabilises an active LBD conformation.
- Coactivator recruitment (notably PGC-1α) is favoured.
- Transcription rises at ERREs → mitochondrial / FAO / exercise genes up.
Inverse agonist path (XCT-790)
- XCT-790 binds ERRα LBD and suppresses constitutive activity — a loss-of-function equivalent.
- Separately, at nanomolar doses, it acts as a mitochondrial electron-transport-chain uncoupler (FCCP-like), collapsing the proton gradient, dropping ATP and activating AMPK — independent of ERRα.
5. SLU-PP-915 Deep Dive
SLU-PP-915 (Compound 10s) is the lead of a 2,5-disubstituted thiophene series designed at Saint Louis University by structure-based optimization from the GSK-4716/ERRγ crystal structure (PDB 2GPP). The innovation: replace the labile acyl-hydrazide / phenol with a boronic acid H-bond donor, preserving activity while improving microsomal stability.
| Parameter | SLU-PP-915 |
|---|---|
| CAS / MW | 2285432-92-8 / 341.16 |
| Isoform EC50 | ERRα 414 nM · ERRβ 435 nM · ERRγ 378 nM |
| Binding validation | 1H NMR ligand titration vs. ERRγ LBD |
| Key up-regulated genes | PPARGC1A, PDK4, LDHA, DDIT4 (C2C12 & mouse quadriceps) |
| Oral bioavailability | Improved vs. SLU-PP-332 (boronic acid metabolic stability) |
| Published readouts | Increased exercise capacity in mice; cardiac remodelling protection |
6. SLU-PP-332 Deep Dive
SLU-PP-332 is the first-generation pan-ERR agonist and the most extensively published in vivo. It defines the field's "exercise mimetic" evidence base.
| Parameter | SLU-PP-332 |
|---|---|
| CAS / MW | 303760-60-3 / 290.32 |
| Isoform EC50 | ERRα 98 nM · ERRβ 230 nM · ERRγ 430 nM |
| Cell readout | 10 µM ↑ mitochondrial respiration in C2C12 myoblasts |
| In vivo (mouse, 50 mg/kg bid) | ↑ oxidative fibres, cytochrome C, mtDNA, running distance & duration, grip strength |
| Metabolic syndrome model | ↓ body weight, fat mass, cholesterol, TG; improved insulin sensitivity; ↓ glucose in GTT (JPET 2024) |
| Aging-kidney model | ↓ albuminuria, kidney weight; ↑ podocin (Am. J. Pathol. 2023) |
| Solubility | DMSO 1–10 mg/mL; ethanol 0.1–1 mg/mL |
7. DY131 (GSK 9089) Deep Dive
DY131 is the tool for ERRβ/γ-selective agonism. It is inactive at ERRα through 30 µM, which lets researchers isolate β/γ biology from the dominant ERRα signal.
| Parameter | DY131 |
|---|---|
| CAS / MW | 95167-41-2 / 311.38 |
| Selectivity | ERRβ/γ agonist; minimal ERRα, ERα, ERβ at ≤30 µM |
| Fold activation | ERRβ 3–4× (10–30 µM); ERRγ 5–6.6× (3–30 µM) |
| Off-target | Smo (Smoothened) antagonist, IC50 ~3.75 µM |
| Research contexts | Prostate / breast cancer, osteoclastogenesis & bone, LPS hepatotoxicity, steroidogenesis |
8. GSK4716 Deep Dive
GSK4716 (originally GlaxoSmithKline) is an ERRβ/γ-directed acyl-hydrazide, often used alongside DY131 as a β/γ agonist reference — but the literature is not perfectly consistent about its directionality.
| Parameter | GSK4716 |
|---|---|
| CAS / MW | 101574-65-6 / 282.34 |
| Primary label | ERRβ/γ agonist, minimal ERRα / ERα / ERβ activity |
| Alternate label | Described as an ERRγ inverse agonist in some vendor/Santa Cruz literature |
| Solubility | DMSO >10 mg/mL |
| Use | β/γ agonist tool; nuclear-receptor chem / SAR reference |
9. XCT-790 Deep Dive — Inverse Agonist & Uncoupler
XCT-790 is the field's standard ERRα inverse agonist (Busch et al., J. Med. Chem. 2004) and the only true inverse agonist in this guide. It is indispensable for ERRα loss-of-function — but its second pharmacology demands careful controls.
| Parameter | XCT-790 |
|---|---|
| CAS / MW | 725247-18-7 / 596.42 |
| Primary action | Selective ERRα inverse agonist |
| Off-target | Mitochondrial ETC uncoupler (FCCP-like), nanomolar, ERRα-independent |
| Downstream | ↓ ATP, ↑ AMPK via uncoupling |
| Use | ERRα knock-down equivalent; mitochondrial-uncoupling control |
10. Isoform Selectivity & Head-to-Head Comparison
| Axis | SLU-PP-915 | SLU-PP-332 | DY131 | GSK4716 | XCT-790 |
|---|---|---|---|---|---|
| ERRα | Agonist (414 nM) | Agonist (98 nM) | Inactive ≤30 µM | Minimal | Inverse agonist |
| ERRβ | Agonist (435 nM) | Agonist (230 nM) | Agonist (3–4×) | Agonist | — |
| ERRγ | Agonist (378 nM) | Agonist (430 nM) | Agonist (5–6.6×) | Agonist / labeled inv. | — |
| Pan vs selective | Pan | Pan | β/γ | β/γ | α-only (inverse) |
| Off-target | None noted | None noted | Smo antagonist | Conflicting label | Mitochondrial uncoupler |
| Oral PK | Improved | Moderate | Preclinical | Preclinical | Preclinical |
| Best fit | Modern pan tool | Reference pan tool | β/γ / cancer | β/γ reference | α loss-of-function |
11. Preclinical Findings Across Models
Exercise capacity & skeletal muscle
Both pan-agonists induce an ERRα-dependent acute aerobic-exercise gene program and increase treadmill running distance, duration and grip strength in mice (SLU-PP-332 at 50 mg/kg bid; SLU-PP-915 across routes). This is the core "exercise mimetic" dataset.
Metabolic syndrome & insulin resistance
SLU-PP-332 (J. Pharmacol. Exp. Ther. 2024) reduced body weight, fat mass, total cholesterol, HDL and triglycerides, and improved glucose tolerance in high-fat-diet obese mice — supporting use in metabolic-syndrome research.
Aging & kidney
SLU-PP-332 reversed mitochondrial dysfunction and inflammation in aged-kidney models (Am. J. Pathol. 2023) — relevant to frailty / senescence research.
Cardiovascular remodelling
SLU-PP-915 improved left-ventricular function and reduced fibrotic remodelling in pressure-overload models, an ERRγ-mediated cardiac-metabolism effect.
Autophagy & cellular maintenance
SLU-PP-915 activated TFEB, raising LAMP1/2, CTSD, MCOLN1 and p62/SQSTM1 — supporting autophagic-flux and lysosomal-biogenesis studies.
Cancer & bone
DY131 shows antiproliferative effects in prostate (ERRγ-dependent) and breast cancer cells, arrests cells in G2/M, and inhibits osteoclastogenesis / LPS bone loss — a β/γ-selective oncology-and-bone tool.
12. Research Applications & Decision Guide
- Define the question. Gain-of-function (agonist) or loss-of-function (inverse agonist)? Pan or single isoform?
- Pick the probe. Pan readout → SLU-PP-332 (reference) or SLU-PP-915 (modern/oral). ERRβ/γ only → DY131 or GSK4716. ERRα suppression → XCT-790.
- Always run a counter-screen. Agonist + XCT-790, or DY131 + an ERRα probe, to confirm ERR-dependence.
- Control off-targets. FCCP/CCCP arm for XCT-790; Smo probe for DY131.
- Match route to PK. 915 for oral/chronic; 332 for established ip/twice-daily in vivo; DY131/GSK4716/XCT-790 for cellular / acute models.
- QC up front. Batch COA (HPLC + NMR + MS); confirm CAS against lot certificate.
- Exercise mimetic / pan metabolic? → SLU-PP-915 (modern) or SLU-PP-332 (reference).
- ERRβ/γ, cancer or bone? → DY131.
- ERRβ/γ agonist reference? → GSK4716.
- ERRα knock-down equivalent / uncoupling control? → XCT-790.
- SAR / nuclear-receptor chem? → run all five as a panel.
13. SAR: From Acyl-Hydrazides to Boronic Acids
The class shows a clean medicinal-chemistry narrative:
- First generation — acyl hydrazides (SLU-PP-332, DY131, GSK4716): naphthalene / diethylamino / isopropyl N-aryl groups tune isoform preference. Hydrazides carry metabolic-liability concerns.
- Second generation — 2,5-disubstituted thiophenes (SLU-PP-915): the boronic acid replaces the phenol/aniline H-bond donor, keeping ERRγ potency while improving microsomal stability and oral exposure.
- Inverse-agonist chemotype (XCT-790): a trifluoromethyl benzyl-ether + thiadiazole acrylamide — a different pocket interaction that suppresses, rather than amplifies, constitutive ERRα activity.
14. Product Quality, Solubility & Sourcing Notes
| Item | Recommendation |
|---|---|
| Purity | ≥98% HPLC baseline; ≥99% for SAR / structural work. |
| Identity | HPLC retention time + 1H NMR + MS — essential given shared acyl-hydrazide scaffolds (DY131 vs GSK4716). |
| Solubility | DMSO stocks standard. SLU-PP-332 sparingly soluble (1–10 mg/mL); DY131 ≥14 mg/mL; GSK4716 >10 mg/mL; XCT-790 & SLU-PP-915 DMSO-soluble. Dilute to ≤0.1% v/v final DMSO. |
| Storage — solid | −20 °C, sealed, desiccated, light-protected. |
| Storage — DMSO stock | −20 °C, light-protected; plan ≤3–6 months; avoid repeated freeze-thaw. |
| Documentation | Batch COA, chromatogram, NMR, MS, residual-solvent & heavy-metal panels on request. |
| Red flags | Missing COA, CAS/scaffold swaps (DY131↔GSK4716), no NMR identity, price far below market. |
NutraBiotech supplies a broad catalog of metabolic and nuclear-receptor research compounds with full batch-specific QC documentation. For ERR-tool availability or custom sourcing of SLU-PP-915, SLU-PP-332, DY131, GSK4716 or XCT-790, contact our technical team. Not all five are stock items at all times — quote before ordering.
15. Frequently Asked Questions
What are ERR (estrogen-related receptor) agonists?
ERRα, ERRβ and ERRγ are orphan nuclear receptors (genes ESRRA, ESRRB, ESRRG) with no known endogenous ligand. They are constitutively active and driven mainly by the coactivator PGC-1α. ERR agonists are synthetic small molecules that bind the receptor ligand-binding domain and amplify ERR-dependent transcription of mitochondrial, oxidative-metabolism and exercise-adaptation genes. "Pan-ERR" agonists activate all three isoforms; subtype-selective tools such as DY131 or XCT-790 isolate individual isoforms.
What is the difference between SLU-PP-915 and SLU-PP-332?
Both are pan-ERRα/β/γ agonists. SLU-PP-332 (CAS 303760-60-3) is the first-generation acyl-hydrazide naphthalene template (EC50 98/230/430 nM). SLU-PP-915 (CAS 2285432-92-8) is a next-generation 2,5-disubstituted thiophene bearing a boronic acid; it retains pan activity (EC50 ~414/435/378 nM) with improved microsomal stability and oral bioavailability, and was validated by 1H NMR ligand-binding to ERRγ. Think of 915 as the more drug-like successor to 332.
What is XCT-790 — is it an agonist or an inverse agonist?
XCT-790 (CAS 725247-18-7) is a selective ERRα INVERSE agonist, not an agonist. It suppresses the constitutively active ERRα and is the standard tool for ERRα knock-down equivalents in cells. Critically, XCT-790 is also a nanomolar mitochondrial electron-transport-chain uncoupler (FCCP-like), independent of ERRα — so any phenotype must be deconvoluted from uncoupling before being attributed to ERRα.
Is DY131 the same as GSK4716?
No. DY131 (CAS 95167-41-2, also GSK 9089) and GSK4716 (CAS 101574-65-6) are both ERRβ/γ-directed agents, but they are chemically distinct. DY131 is an ERRβ/γ-selective agonist that is inactive at ERRα up to 30 µM and also antagonizes Smoothened (Smo). GSK4716 is an ERRβ/γ agonist with minimal ERRα activity, originally from GlaxoSmithKline. Some vendor literature additionally labels GSK4716 an ERRγ inverse agonist — a characterization conflict worth noting when designing controls.
Are ERR agonists exercise mimetics?
In preclinical models, yes. SLU-PP-332 and SLU-PP-915 induce an ERRα-dependent acute aerobic-exercise gene program, increase oxidative muscle fibres, cytochrome C, mtDNA and running distance/duration in mice. That is why the class is widely described as "exercise mimetics." These are research observations in animals — there is no approved human "exercise pill" and no human clinical data as of 2026.
Are pan-ERR agonists banned by WADA?
ERRα/β/γ agonists are not individually named on the current WADA Prohibited List. However, because compounds such as SLU-PP-332 and SLU-PP-915 act as exercise mimetics and may enhance endurance, athletes subject to anti-doping rules should treat them as high-risk gray-zone agents and verify status via GlobalDRO before any sport-adjacent research.
What are the preclinical research applications of ERR agonists?
Documented research contexts include exercise-mimetic / endurance models, mitochondrial biogenesis, metabolic syndrome and insulin resistance (SLU-PP-332), aging kidney (SLU-PP-332), cardiovascular / pressure-overload remodelling (SLU-PP-915), autophagy / lysosomal biogenesis via TFEB (SLU-PP-915), prostate and breast cancer cell biology (DY131), and osteoclastogenesis / bone protection (DY131). XCT-790 is used for ERRα-specific loss-of-function and as a mitochondrial-uncoupling control.
What is the best ERR agonist for receptor-selectivity work?
For pan-ERR readouts use SLU-PP-332 or SLU-PP-915. For ERRβ/γ-specific agonism use DY131 or GSK4716. For ERRα-specific suppression use XCT-790. Pair agonists with the inverse agonist as a counter-screen to confirm ERR-dependence of any transcriptional phenotype.
How soluble and how should these ERR compounds be stored?
Most are DMSO-soluble solids. SLU-PP-332 is sparingly soluble in DMSO (1–10 mg/mL); DY131 ≥14 mg/mL in DMSO; GSK4716 >10 mg/mL in DMSO; XCT-790 and SLU-PP-915 are DMSO-soluble. Store powders sealed, desiccated, protected from light at −20 °C; prepare DMSO stocks protected from light and freeze. Always confirm identity by batch-specific COA (HPLC + NMR/MS).
Is there any human clinical data on these compounds?
No. As of September 2026, none of the five compounds has entered human clinical trials. All data are in vitro, ex vivo and animal (mouse) models. They are research chemicals only, not approved for human or veterinary use by the FDA, EMA, PMDA or any other agency.
Need ERR / Metabolic Research Compounds?
NutraBiotech supplies nuclear-receptor and metabolic research chemicals with full batch-specific COA (HPLC + NMR + MS). For SLU-PP-915, SLU-PP-332, DY131, GSK4716 or XCT-790 availability and custom sourcing, talk to our technical team.
Request a Quote →16. Conclusion
The ERR toolbox lets a researcher interrogate energy metabolism at isoform resolution. SLU-PP-915 and SLU-PP-332 are the pan-agonists — 332 the validated reference, 915 the more drug-like, orally active successor. DY131 and GSK4716 isolate ERRβ/γ (with DY131 also hitting Smo, and GSK4716 carrying a conflicting inverse-agonist label in parts of the literature). XCT-790 is the indispensable ERRα inverse agonist — but its mitochondrial-uncoupling activity means every result needs an FCCP/CCCP control.
For study design: anchor with a pan-agonist, confirm with an isoform-selective partner, and always pair agonists with the XCT-790 inverse agonist as a counter-screen. Keep identity confirmed at the COA level — especially across the shared acyl-hydrazide scaffolds (DY131 vs. GSK4716). And remember: the "exercise pill" headline is preclinical only; there is no approved human equivalent and no human trial data as of 2026.