The Right Target, The Right Chemistry, The Right Time
HDAC6 isn’t like other HDACs. While most histone deacetylases act in the nucleus to regulate gene expression, HDAC6 is a unique, cytoplasmic enzyme that modulates a wide range of disease-relevant processes—including axonal transport, protein clearance, autophagy, oxidative stress, inflammation, and stress granule formation.
In neurons, HDAC6 plays a pivotal role in maintaining axonal health by regulating the acetylation of α-tubulin, a key component of the microtubule network responsible for transporting important organelles like mitochondria, lysosomes, and endosomes. Dysfunctional HDAC6 activity disrupts this transport system, leading to cellular stress, protein aggregation, and ultimately neurodegeneration.
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Why Inhibit HDAC6?
Selective HDAC6 inhibition (HDAC6i) offers a promising way to reverse or prevent the underlying cellular damage seen in a range of neurodegenerative and neuromuscular diseases. Numerous preclinical studies—despite being conducted with suboptimal compounds which would not be suitable for long term clinical testing—have demonstrated the potential of HDAC6i to restore axonal transport, improve neuronal function, and reduce inflammation.
Augustine’s Approach
At Augustine Therapeutics, we’ve developed a novel generation of small molecule HDAC6 inhibitors with a unique, non-hydroxamate, non-hydrazide chemotype—built for long-term use in chronic diseases. These compounds are highly selective, orally bioavailable, and designed with safety and pharmacokinetics in mind.
This next-generation chemistry enables us to pursue disease-modifying therapies across a spectrum of indications, starting with Charcot-Marie-Tooth disease (CMT).
"This new generation of selective, orally bioavailable, and safe HDAC6i represents a life-changing breakthrough for patients suffering from neuromuscular and neurodegenerative diseases. In both disease mouse models, we saw a robust reversal of the disease, providing a disease-modifying therapy and potential cure for such disabling disorders. These discoveries will have a tremendous impact on patients worldwide”
Where HDAC6 Matters
Our lead program, AGT-100XXX, is in IND-enabling studies and is under evaluation for potential clinical studies in several neuromuscular and cardiometabolic indications, but our pipeline doesn’t stop there. We’re advancing a portfolio designed to maximize the therapeutic potential of HDAC6 across a broad spectrum of potential diseases.
Neuromuscular Diseases
Duchenne Muscular Dystrophy
A severe, rare genetic disorder causing progressive muscle degeneration and weakness, primarily in boys. A non-selective HDAC inhibitor has been approved as a treatment in patients 6 years and older.
Charcot-Marie-Tooth Disease (CMT)
A progressive, hereditary neuropathy affecting >2.5m people worldwide, causing muscle weakness, numbness, and chronic pain. No approved treatments exist. HDAC6i has been shown to reverse disease progression in preclinical models.
Chemotherapy-Induced Peripheral Neuropathy (CIPN)
In preclinical studies, HDAC6 inhibitors have been shown to produce not only a robust curative but also a preventive effect for CIPN.
Cardiometabolic Diseases
Heart Failure with Preserved Ejection Fraction (HFpEF)
A syndrome with diverse pathophysiological mechanisms (diastolic dysfunction, systemic inflammation, endothelial dysfunction) affecting >25m people worldwide. Inhibiting HDAC6 effectively reverses established heart failure in HFpEF mouse models.
Atrial Fibrillation
Irregular heartbeat (arrhythmia) affecting >44m people worldwide. Experimental in vivo/ex vivo data with HDAC6i validate its potential in Atrial Fibrillation (AF). Cellular effects suggest disease modification potential.
Neurodegenerative Diseases
Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s Disease (AD), and beyond
Similar to what is observed in peripheral neuropathies, HDAC6 inhibitors are very effective in restoring axonal transport in diseased neurons of the central nervous system. Preclinical models show the potential of HDACi in diseases such as ALS, AD, and Parkinson’s Disease. Augustine is developing brain-penetrant HDAC6i for neurodegenerative diseases.
