Cardiac toxicity
cAMP/PKA signaling increases contractility, causes hypertrophy and arrhythmia risk. Tolerability concerns with chronic dosing.
Science · Published in Cell
GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
This paper demonstrates that GRK2 functions as a signaling protein — not merely a desensitizing kinase — enabling a first-in-class oral therapeutic that drives insulin-independent glucose uptake in skeletal muscle without cardiac toxicity or receptor desensitization.
CellVolume 188, Issue 19 · June 23, 2025 · Pages 5142–5156.e23
Motso, NL et al. · Stockholm University · Karolinska Institutet · Atrogi AB
Read original paper 01 · The problem
Why β₂-agonists have failed for six decades.
The β₂-adrenergic receptor in skeletal muscle is one of the most powerful metabolic regulators in the human body. Activating it drives glucose uptake, fat oxidation, and muscle growth — essentially mimicking the metabolic effects of exercise.
Yet for six decades, every attempt to use β₂-agonists therapeutically for metabolic disease has failed. The classical signaling cascade that drives metabolic benefit — Gs→cAMP/PKA — also causes cardiac hypertrophy, arrhythmia, and tachycardia. Worse, the receptor desensitizes rapidly through GRK2-mediated β-arrestin recruitment, meaning efficacy fades within days.
Clenbuterol. Salbutamol. Formoterol. All failed for the same two reasons: cardiac toxicity and tachyphylaxis. The field concluded that these could not be separated. Motso et al. proved that wrong.
Desensitization
GRK2 phosphorylates C-terminus → β-arrestin → receptor internalization. Drug stops working in days.
The insight
What if GRK2 could be recruited WITHOUT triggering C-terminal phosphorylation or β-arrestin?
02 · The discovery
A non-canonical signaling complex.
Using a hybrid target-based phenotypic screen — measuring glucose uptake and cAMP simultaneously — Atrogi identified compounds that activate metabolic pathways while generating almost no cardiac-risk signaling. ATR-258 stabilizes a unique β₂AR/GRK2 complex with three unprecedented properties:
01
Minimal cAMP
Preferentially recruits GRK2 over Gs protein, generating almost no cAMP/PKA — eliminating cardiac toxicity at its source.
02
No C-terminal phosphorylation
GRK2 does NOT phosphorylate the receptor's C-terminus — a striking departure from 30 years of pharmacological dogma.
03
No desensitization
Without C-terminal phosphorylation, β-arrestin is never recruited. Receptor stays on membrane. No tachyphylaxis. Durable efficacy.
Non-canonical pathway (ATR-258)
ActivatedNot activated
ATR-258
Oral, once-daily
pEC₅₀ = 6.87
β₂-AR
GRK2-biased binding
Preferential over Gs
- Gs → cAMPCardiac signaling
GRK2
Non-canonical complex
No C-terminal phos.
- β-arrestinRecruitment
- InternalizationDesensitization
mTORC2
Insulin-independent
Validated by knockdown
GLUT4
Translocation
Muscle glucose uptake
Key finding
p = 0.0015
Significant negative correlation between GRK2 efficacy and β-arrestin2 recruitment (p = 0.0015), overturning the textbook model that GRK2 necessarily promotes β-arrestin binding.
03 · Chemistry
A platform designed for precision.
Atrogi's chemistry platform doesn't just find active molecules — it engineers selectivity by design. Using computational modeling and structure-guided modifications, our team can precisely tune which signaling pathways a compound activates and which it avoids.
The result is a growing library of thousands of rationally designed compounds, each with a distinct signaling fingerprint. This platform — protected by 40+ granted patents — gives Atrogi the ability to develop candidates tailored to multiple indications, from metabolic disease to muscle wasting.
ATR-258 signaling profile
GRK2 recruitment92%
Glucose uptake efficacy88%
cAMP generation15%
β-arrestin2 recruitment3%
β₁AR agonism0%
Relative to isoprenaline (normalized).
04 · In vivo data
Preclinical evidence across metabolic models.
Diet-induced obesity mice — 18-day oral treatment
7/7
metabolic endpoints improvedHeart weight unchanged
- Glucose toleranceImproved
- Fat massReduced
- Insulin sensitivityImproved
- O₂ consumptionIncreased
- Energy expenditureIncreased
- Ectopic lipidReduced
- Islet morphologyImproved
- Heart weightNo change
0.3 or 0.1 mg/kg daily oral gavage · n = 6–10/group · Two-way ANOVA with FDR correction
Cardiac safety — human atrial tissue
Salbutamol / Clenbuterol (Gs-biased)ATR-258 (GRK2-biased)
| Measure | Salbutamol / Clenbuterol | ATR-258 |
|---|---|---|
| Contractile force | 78% | 8% |
| Heart weight | 65% | 0 |
No myocardial lesions in long-term tox
The muscle-sparing combination: ATR-258 + liraglutide
Liraglutide alone
- FatReduced
- Lean massLost
Confirms GLP-1 muscle wasting
ATR-258 alone
- FatReduced
- Lean massIncreased
Muscle sparing + glucose lowering
Combination
- FatGreater reduction
- Lean massPreserved
Best of both — no muscle loss
05 · Clinical data
Phase I confirmed safety in 69 human subjects.
ATTRACTIVE 1 (NCT05409924) — first-in-human, Phase 1a/b, randomized, double-blind, placebo-controlled. Conducted at CRS Mannheim, Germany. First patient January 2023, results March 2024.
Total subjects
CV safety confirmed
QD
Oral dosing
Part A
SAD
Healthy volunteers
Single ascending doses
Part B
MAD
Healthy volunteers
Multiple ascending doses
Part C
Patient cohort
23 patients (15:8 ratio)
2.5 mg QD × 28 days
Phase II program
ATTRACTIVE 3
Proof-of-conceptBody composition (DXA/MRI), muscle mass/function, metabolic parameters, mitochondrial biomarkers in healthy volunteers.
ATTRACTIVE 4
GLP-1 combinationATR-258 as add-on to GLP-1 agonists in obese patients. The definitive muscle-sparing study.
Publications
Key publications.
2026Nature CommunicationsProlonged β2-agonist treatment enhances muscle-specific glucose uptake in individuals with overweight and obesity: a randomized placebo-controlled trialVan Lier et al.2025CellGRK-biased adrenergic agonists for T2D and obesityMotso LR et al. · 188(19):5142–5156.e232024ADAATR-258 Is a Precision Modulator of β₂-AR Signaling (1883-LB)2024Mol MetabThe novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis 2020Diabetologia Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity Kalinovich et al., 2014DiabetelogiaImproving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscleSaato et al.,
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Atrogi's research spans academic institutions, clinical organizations, and CROs across the world — from receptor pharmacology in Melbourne to muscle biology in Padova.
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