ATX-304 (Sodium Salt)

ATX-304 (O304) is a synthetic small molecule that activates AMP-activated protein kinase (AMPK), the cell's energy sensor. Researchers at Umeå University and Betagenon AB in Sweden found it in a cell-based screen and called it a pan-AMPK activator (Steneberg et al., 2018).

Later papers use the code ATX-304: one calls it "formerly O304" (Holm et al., 2025), and another says Amplifier Therapeutics (Betagenon) supplied it (Katerelos et al., 2024).

The page lists CAS 1261289-04-6, C₁₆H₁₁Cl₂N₃O₂S and 380.2 g/mol, which PubChem CID 50923806 gives for the free compound; that record is also the source of the aliases and structure.

Published work on ATX-304 and O304 falls into six areas. Apart from one 28-day trial, the evidence comes from cells, tissues and animals, and six of the eleven primary papers involve Betagenon through a co-founder author or supplied compound.

Discovery and mechanism

The discovery paper reported that O304 raised AMPK phosphorylation at threonine 172 in cells without lowering cellular ATP. In cell-free assays it suppressed PP2C-mediated dephosphorylation of that site on human AMPK trimers without inhibiting PP2C itself, and it did not activate AMPK allosterically. In cells it needed the upstream kinase LKB1 and worked with either β1 or β2 subunits (Steneberg et al., 2018).

The same group later reported mitochondrial uncoupling in myotubes (Norlin et al., 2023), and an independent group confirmed it in A10 and HepG2 cells, where it lowered mitochondrial membrane potential and activated AMPK (Li et al., 2025). Models: recombinant protein, cell lines and myotubes.

Glucose control and beta cells in diabetic mouse models

In diet-induced obese mice gavaged with 100 mg/kg per day for 8 weeks, O304 alone or with metformin prevented the rise in fasting glucose, insulin and HOMA-IR, and in the diet it reduced islet amyloid in hIAPP transgenic mice (Steneberg et al., 2018).

In CBA mice on a high-fat diet, it largely prevented diet-linked changes in islet gene expression and chromatin marks, including the beta-cell stress marker Aldh1a3 (López-Pérez et al., 2021). In streptozotocin diabetic mice it raised muscle glucose uptake, restored heart glucose uptake and lowered glycogen build-up, and in db/db mice it preserved beta-cell mass and insulin secretion (Norlin et al., 2023). Models: mice and islets.

Heart and blood vessels

In diet-induced obese mice fed O304, cardiac glucose uptake rose, heart glycogen fell and stroke volume rose by about 20%, with no increase in heart weight; rats gavaged for six months at 100 to 600 mg/kg per day showed no rise in heart-to-brain weight ratio (Steneberg et al., 2018).

In streptozotocin diabetic mice, one week on an O304 diet raised the E/A ratio and shortened isovolumetric relaxation time, which the authors call reversal of diabetic cardiomyopathy (Norlin et al., 2023). In ApoE-deficient mice given angiotensin II, 200 mg/kg orally reduced aneurysm formation and blood pressure (Sun et al., 2024). Models: mice and rats.

Aging models

In male F1 hybrid mice fed O304 from 6 or 12 months of age, it prevented and reversed age-associated insulin resistance, raised stroke volume and cardiac output on echocardiography, raised myocardial capillary density and lengthened treadmill running distance to exhaustion. Heart weight was 15% higher after six months, without more fibrosis or glycogen, and the authors call O304 an exercise mimetic (Ericsson et al., 2021).

In 18-month-old mice with one kidney removed, 10 mg/kg per day intraperitoneally for 12 weeks reduced renal senescence and fibrosis markers (Zhu et al., 2022). At 100 micromolar it extended C. elegans lifespan through the AMPK-mTOR axis (Li et al., 2025). Models: mice and nematodes.

Liver, kidney injury and pain models

In male C57BL/6J mice on a choline-deficient high-fat diet, a model of fatty liver disease (MASLD), ATX-304 at 1 mg/g of diet for 7 to 24 weeks reduced steatosis and fibrosis development and lowered blood cholesterol, with more fatty acid oxidation and uneven effects between liver lobes (Holm et al., 2025).

Mice fed ATX-304 chow for 7 days before cisplatin had lower serum creatinine, NGAL and histological injury, and its protection of cultured cells was lost in AMPK-null fibroblasts (Katerelos et al., 2024). In mouse pain models, 200 mg/kg by gavage reduced mechanical hypersensitivity after hind-paw incision (Das et al., 2019) and allodynia after lumbar disk puncture, with an ED50 of 140 mg/kg (Das et al., 2022). Models: mice and kidney cells.

The phase IIa trial in type 2 diabetes

The only published human data come from TELLUS, an exploratory, randomized, double-blind 28-day phase IIa study comparing one daily amount of O304 with placebo in 65 people with type 2 diabetes on metformin (Steneberg et al., 2018). In a post hoc subgroup, fasting glucose fell by 0.60 mmol/L on O304 versus 0.10 on placebo.

Across the O304 group, systolic and diastolic blood pressure fell by 5.8 and 3.8 mmHg against small rises on placebo, and MRI showed more calf muscle perfusion. The authors called the glucose change modest, noted a weight imbalance between groups, and reported O304 as well tolerated. Model: people with type 2 diabetes.